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Vascular Oxidative Stress and Endothelial Dysfunction in Patients With Chronic Heart Failure Role of Xanthine-Oxidase and Extracellular Superoxide Dismutase
Abstract
Impaired flow-dependent, endothelium-mediated vasodilation (FDD) in patients with chronic heart failure (CHF) results, at least in part, from accelerated degradation of nitric oxide by oxygen radicals. The mechanisms leading to increased vascular radical formation, however, remain unclear. Therefore, we determined endothelium-bound activities of extracellular superoxide dismutase (ecSOD), a major vascular antioxidant enzyme, and xanthine-oxidase, a potent radical producing enzyme, and their relation to FDD in patients with CHF.
ecSOD and xanthine-oxidase activities, released from endothelium into plasma by heparin bolus injection, were determined in 14 patients with CHF and 10 control subjects. FDD of the radial artery was measured using high-resolution ultrasound and was assessed before and after administration of the antioxidant vitamin C (25 mg/min; IA). In patients with CHF, endothelium-bound ecSOD activity was substantially reduced (5.0+/-0.7 versus 14.4+/-2.6 U x mL(-1) x min(-1); P<0.01) and closely related to FDD (r=0.61). Endothelium-bound xanthine-oxidase activity was increased by >200% (38+/-10 versus 12+/-4 nmol O2*- x microL(-1); P<0.05) and inversely related to FDD (r=-0.35) in patients with CHF. In patients with low ecSOD and high xanthine-oxidase activity, a greater benefit of vitamin C on FDD was observed, ie, the portion of FDD inhibited by radicals correlated negatively with ecSOD (r=-0.71) but positively with xanthine-oxidase (r=0.75).
These results demonstrate that both increased xanthine-oxidase and reduced ecSOD activity are closely associated with increased vascular oxidative stress in patients with CHF. This loss of vascular oxidative balance likely represents a novel mechanism contributing to endothelial dysfunction in CHF.
... Declining left ventricular ejection fraction(LVEF) (below 45%) has been reported to be an important and powerful predictor of cardiovascular outcomes, including heart failure (HF) hospitalization, and cardiovascular mortality in the course of myocardial infarction [6][7][8]. Superoxide dismutase (SOD) has been studied to identify subgroups of patients at high risk of HF [9,10], although cardiac troponins and natriuretic peptides are the most widely used predictive biomarkers in the management of HF [11]. Although a study has recently shown that SOD is a potential link between LV structural remodeling and the subsequent development of HF in patients with CVD [12], the relationship between SOD and LVEF has not been evaluated in the diabetic patients with ACS. ...
... Furthermore, gene-deficient mice lacking SOD and exposed to cardiac injury have demonstrated worse outcomes than wild-type mice [19], whereas mice overexpressing SOD and exposed to ischemia/reperfusion injury were found to have severely decreased levels of superoxide production, improved contractile function, and a decreased in infarct size [20]. Population studies have reported that the reduced SOD activity is closely associated with the increased vascular oxidative stress, which likely contributes to endothelial dysfunction in patients with HF [9]. The results from the most recent cross-sectional study showed that SOD activity is a potential link between left ventricular structural remodeling and the subsequent development of HF in patients with cardiovascular disease [12]. ...
... No adjusted, simple logistic regression; Model 1, multiple logistic regression adjusted for gender, smoking habits, systolic blood pressure; Model 2, multiple logistic regression, using a forward stepwise procedure to select variables, further adjusted for alanine aminotransferase (ALT), high density lipoprotein cholesterol (HDL-C), fasting blood glucose (FBG), HbA1c, serum creatinine (Cr), serum uric acid (UA), NT-proBNP and hs-cTnT. a The OR was examined by regarding the lowest quartiles as reference; b The HR was examined by evaluating 1 normalized unit increase Molecular genetic studies have shown that a singlebase substitution causing the exchange of glycine for argi-nine213 (Arg213Gly) in the heparin binding domain of SOD is associated with markedly increased plasma concentrations of the enzyme [9][10][11]. Previous studies have shown that SOD mutation is associated with excessive oxidative stress, endothelial dysfunction, and increased risk of ischemic heart disease [21,22]. ...
Aim
To examine the prognostic value of superoxide dismutase (SOD) activity for monitoring reduced left ventricular ejection fraction(LVEF)in the patients with type 2 diabetes and acute coronary syndrome (ACS).
Methods
The population of this cross-sectional study included 2377 inpatients with type 2 diabetes who had an ACS admitted to the Shandong Provincial Hospital Affiliated to Shandong First Medical University from January 2016 to January 2021.
Results
Diabetic patients with ACS were divided into 2 subgroups based on LVEF. The mean SOD activity was significantly lower in patients with an LVEF ≤ 45% than in those with an LVEF > 45% (149.1 (146.4, 151.9) versus 161.9 (160.8, 163.0)). Using ROC statistic, a cut-off value of 148.8 U/ml indicated an LVEF ≤ 45% with a sensitivity of 51.6% and a specificity of 73.7%. SODs activity were found to be correlated with the levels of NT-proBNP, hs-cTnT, the inflammatory marker CRP and fibrinogen. Despite taking the lowest quartile as a reference (OR 0.368, 95% CI 0.493–0.825, P = 0.001) or examining 1 normalized unit increase (OR 0.651, 95% CI 0.482–0.880, P = 0.005), SOD activity was found to be a stronger predictor of reduced LVEF than CRP and fibrinogen, independent of confounding factors.
Conclusions
Our cross-sectional study suggests that SOD activity might be a valuable and easily accessible tool for assessing and monitoring reduced LVEF in the diabetic patients with ACS.
... [1][2][3][4][5] UA may also be increased because of increased production due to greater xanthine oxidase activity in patients with heart failure. 6,7 As a result, hyperuricaemia is common in heart failure and higher UA is associated with worse clinical outcomes. [8][9][10][11] The association between higher UA and worse outcomes persists after adjustment for renal function, diuretic use and dose, and natriuretic peptide levels. ...
... [9][10][11] Whether this is due to unmeasured confounding, or a directly injurious effect of UA is unknown. [1][2][3][4][5][6][7][8][9][10][11] However, UA increases cytokine and chemokine production, promotes inflammation, impairs endothelial function and activates the renin-angiotensin system. [1][2][3][4][5][6][7][8][9][10][11] In addition, UA may be a marker of oxidative stress as xanthine oxidase generates superoxide along with UA. [1][2][3][4][5][6][7][8][9][10][11] Hyperuricaemia can also lead to . ...
... [1][2][3][4][5][6][7][8][9][10][11] However, UA increases cytokine and chemokine production, promotes inflammation, impairs endothelial function and activates the renin-angiotensin system. [1][2][3][4][5][6][7][8][9][10][11] In addition, UA may be a marker of oxidative stress as xanthine oxidase generates superoxide along with UA. [1][2][3][4][5][6][7][8][9][10][11] Hyperuricaemia can also lead to . gout which is common in patients with heart failure, is difficult to manage and may lead to and prolong hospitalization. ...
Aims:
Blood uric acid (UA) levels are frequently elevated in patients with heart failure and reduced ejection fraction (HFrEF), may lead to gout and are associated with worse outcomes. Reduction in UA is desirable in HFrEF and sodium-glucose cotransporter 2 inhibitors may have this effect. We aimed to examine the association between UA and outcomes, the effect of dapagliflozin according to baseline UA level, and the effect of dapagliflozin on UA in patients with HFrEF in the DAPA-HF trial.
Methods and results:
The association between UA and the primary composite outcome of cardiovascular death or worsening heart failure, its components, and all-cause mortality was examined using Cox regression analyses among 3119 patients using tertiles of UA, after adjustment for other prognostic variables. Change in UA from baseline over 12 months was also evaluated. Patients in tertile 3 (UA ≥6.8 mg/dl) versus tertile 1 (<5.4 mg/dl) were younger (66.3 ± 10.8 vs. 68 ± 10.2 years), more often male (83.1% vs. 71.5%), had lower estimated glomerular filtration rate (58.2 ± 17.4 vs. 70.6 ± 18.7 ml/min/1.73 m2 ), and more often treated with diuretics. Higher UA was associated with a greater risk of the primary outcome (adjusted hazard ratio tertile 3 vs. tertile 1: 1.32, 95% confidence interval [CI] 1.06-1.66; p = 0.01). The risk of heart failure hospitalization and cardiovascular death increased by 7% and 6%, respectively per 1 mg/dl unit increase of UA (p = 0.04 and p = 0.07). Spline analysis revealed a linear increase in risk above a cut-off UA value of 7.09 mg/dl. Compared with placebo, dapagliflozin reduced UA by 0.84 mg/dl (95% CI -0.93 to -0.74) over 12 months (p < 0.001). Dapagliflozin improved outcomes, irrespective of baseline UA concentration.
Conclusion:
Uric acid remains an independent predictor of worse outcomes in a well-treated contemporary HFrEF population. Compared with placebo, dapagliflozin reduced UA and improved outcomes irrespective of UA concentration.
... Exploring the prognostic role of sUA is of particular interest in the case of HF, as sUA is frequently increased in this condition [4]. Interestingly, high sUA in HF may reflect a specific metabolic alteration, since the UA-forming enzyme xanthine-oxidase (XO) is overexpressed in HF patients [5][6][7], thus providing a mechanistic explanation for elevated sUA levels. Indeed, high sUA concentrations are strongly associated with disease severity and mortality in HF, regardless of setting, i.e., outpatients [8][9][10][11][12][13][14], hospitalized patients [15][16][17][18], myocardial infarction complicated by left ventricular dysfunction [19]. ...
... In this context, increased sUA can be regarded as a biomarker reflecting increased XO activity, and hence ongoing greater production of oxidants in the vasculature, XO being particularly abundant at vascular level [5]. Interestingly, this possibility would explain the disconnect between renal function and sUA prognostic role, as what may matter would not be the absolute sUA concentration per se, but rather its production via an enzymatic pathway that results in oxidants formation [36]. ...
... Interestingly, this possibility would explain the disconnect between renal function and sUA prognostic role, as what may matter would not be the absolute sUA concentration per se, but rather its production via an enzymatic pathway that results in oxidants formation [36]. This mechanism can be of particular relevance in the case of HF patients, in whom large overexpression of XO activity has been documented [5][6][7]; increased XO activity may contribute to the pathophysiology of HF via increased oxidant formation, which may cause cardiac mechano-energetic uncoupling and vascular dysfunction [5,20,[36][37][38][39][40]. While targeting uric acid in HF has so far provided inconclusive results in HFrEF [40], it might be a potentially useful approach in HFpEF or HFmrEF. ...
Background
Retrospective analyses of clinical trials indicate that elevated serum uric acid (sUA) predicts poor outcome in heart failure (HF). Uric acid can contribute to inflammation and microvascular dysfunction, which may differently affect different left ventricular ejection fraction (LVEF) phenotypes. However, role of sUA across LVEF phenotypes is unknown.
Objectives
We investigated sUA association with outcome in a prospective cohort of HF patients stratified according to LVEF.
Methods
Through the Heart Failure Long-Term Registry of the European Society of Cardiology (ESC-EORP-HF-LT), 4,438 outpatients were identified and classified into: reduced (<40% HFrEF), mid-range (40–49% HFmrEF), and preserved (≥50% HFpEF) LVEF. Endpoints were the composite of cardiovascular death/HF hospitalization, and individual components.
Results
Median sUA was 6.72 (IQ:5.48-8.20) mg/dl in HFrEF, 6.41 (5.02-7.77) in HFmrEF, and 6.30 (5.20-7.70) in HFpEF. At a median 372-day follow-up, the composite endpoint occurred in 648 (13.1%) patients, with 176 (3.6%) deaths and 538 (10.9%) HF hospitalizations. Compared with lowest sUA quartile (Q), Q-III and Q-IV were significantly associated with the composite endpoint (adjusted HR 1.68: 95% CI 1.11–2.54; 2.46: 95% CI 1.66–3.64, respectively). By univariable analyses, HFrEF and HFmrEF patients in Q-III and Q-IV, and HFpEF patients in Q-IV, showed increased risk for the composite endpoint (P<0.05 for all); after model-adjustment, significant association of sUA with outcome persisted among HFrEF in Q-IV, and HFpEF in Q-III-IV.
Conclusions
In a large, contemporary-treated cohort of HF outpatients, sUA is an independent prognosticator of adverse outcome, which can be appreciated in HErEF and HFpEF patients.
... The total score of the questionnaire ranges from 1 to 25, with higher scores indicating better erectile function. Accordingly, the SHIM score is divided into five categories: severe ED (1-7), moderate ED (8-11), mildmoderate ED (12)(13)(14)(15)(16), mild ED (17)(18)(19)(20)(21), and non-ED (22)(23)(24)(25). 15 ...
... 22,23 The imbalance between vasoconstriction and vasodilation caused by endothelial dysfunction leads to excessive systemic vasoconstriction and decreased peripheral tissue perfusion in HF patient. 24,25 Indeed, most HF patients may suffer from ED, 8,26 and in our study, 90% of HF patients were diagnosed with EDs of various severities. ...
... So, most recent studies on this topic focus on how we can improve our understanding of heart failure syndrome and its complexity besides new approaches for its prevention and therapy. Since increasing events demonstrate an important contribution of increased oxidative stress in the pathology of heart failure [2][3][4], in these regards, there are some studies to demonstrate that antioxidants represent a credible therapeutic approach to preventing heart failure progress and improving its outcome [5][6][7][8][9][10]. However, there is some inconsistency among clinical studies. ...
... These two compounds are known in the category of polyphenols or plant micronutrients which have health benefits like defense against oxidative stress besides other actions [19][20][21]. Indeed, increasing events demonstrate the contribution of increased oxidative stress in the pathology of heart failure [2][3][4], and therefore, antioxidants represent a credible therapeutic approach to preventing heart failure progress [5][6][7][8][9][10]. Among their actions, there is mainly the prevention of glucose intolerance and neutralizing oxidants such as superoxide, peroxynitrite, and H 2 O 2 [66]. ...
Doxorubicin (DOXO) induces marked cardiotoxicity, though increased oxidative stress while there are some documents related with cardioprotective effects of some antioxidants against organ-toxicity during cancer treatment. Although magnolia bark has some antioxidant-like effects, its action in DOXO-induced heart dysfunction has not be shown clearly. Therefore, here, we aimed to investigate the cardioprotective action of a magnolia bark extract with active component magnolol and honokiol complex (MAHOC; 100 mg/kg) in DOXO-treated rat hearts. One group of adult male Wistar rats was injected with DOXO (DOXO-group; a cumulative dose of 15 mg/kg in 2-week) or saline (CON-group). One group of DOXO-treated rats was administered with MAHOC before DOXO (Pre-MAHOC group; 2-week) while another group was administered with MAHOC following the 2-week DOXO (Post-MAHOC group). MAHOC administration, before or after DOXO, provided full survival of animals during 12–14 weeks, and significant recoveries in the systemic parameters of animals such as plasma levels of manganese and zinc, total oxidant and antioxidant statuses, and also systolic and diastolic blood pressures. This treatment also significantly improved heart function including recoveries in end-diastolic volume, left ventricular end-systolic volume, heart rate, cardiac output, and prolonged P-wave duration. Furthermore, the MAHOC administrations improved the structure of left ventricles such as recoveries in loss of myofibrils, degenerative nuclear changes, fragmentation of cardiomyocytes, and interstitial edema. Biochemical analysis in the heart tissues provided the important cardioprotective effect of MAHOC on the redox regulation of the heart, such as improvements in activities of glutathione peroxidase and glutathione reductase, and oxygen radical-absorbing capacity of the heart together with recoveries in other systemic parameters of animals, while all of these benefits were observed in the Pre-MAHOC treatment group, more prominently. Overall, one can point out the beneficial antioxidant effects of MAHOC in chronic heart diseases as a supporting and complementing agent to the conventional therapies.
... Oxidative damage induced by reactive oxygen species (ROS) has been implicated in the pathogenesis of diabetic cardiomyopathy [5][6][7]. ROS is mainly produced by mitochondria, NADPH oxidase and xanthine oxidase in the heart [8,9]. Inhibition of xanthine oxidase or NADPH oxidase reduces diabetic cardiomyopathy [10][11][12]. ...
Introduction: The mitochondria are important sources of reactive oxygen species (ROS) in the heart. Mitochondrial ROS production and subsequent oxidative damage have been implicated in the pathogenesis of diabetic cardiomyopathy. We hypothesized that therapeutic strategies specifically targeting mitochondrial ROS may have benefit in diabetic cardiomyopathy.
Hypothesis: We hypothesized that therapeutic inhibition of mitochondrial ROS with mito-TEMPO reduces diabetic cardiomyopathy.
Methods: The mitochondria-targeted antioxidant mito-TEMPO was administrated after diabetes onset in a mouse model of streptozotocin (STZ)-induced type-1 diabetes and type-2 diabetic db/db mice. Cardiac adverse changes were analyzed and myocardial function assessed. Cultured adult cardiomyocytes were stimulated with high glucose, and single mitochondrial superoxide generation and cell death were measured.
Results: Incubation with high glucose increased mitochondria superoxide generation in cultured adult cardiomyocytes, which was prevented by mito-TEMPO. Co-incubation with mito-TEMPO also abrogated high glucose-induced cell death. Mitochondrial ROS generation, and intracellular ROS formation and oxidative damage were induced in both type-1 and type-2 diabetic mouse hearts. Daily injection of mito-TEMPO for 30 days inhibited mitochondrial ROS generation, prevented intracellular ROS formation and oxidative damage, decreased apoptosis and reduced myocardial hypertrophy in diabetic hearts without change of blood glucose, leading to improvement of myocardial function in both type-1 and type-2 diabetic mice. Mechanistic study revealed that the protective effects of mito-TMEPO were associated with down-regulation of ERK1/2 phosphorylation in diabetic hearts and high glucose-stimulated cardiomyocytes.
Conclusions: Therapeutic inhibition of mitochondrial ROS by mitochondria-targeted antioxidant mito-TEMPO reduced adverse cardiac changes and mitigated myocardial dysfunction in both type-1 and type-2 diabetic mice. Thus, mitochondria-targeted antioxidants may be an effective therapy for diabetic cardiac complications.
... Recent studies indicated that inflammation and oxidative stress predisposed individuals to CVDs and diabetes (6). The serum pro-oxidant-antioxidant balance (PAB) assay is a quick, cheap, and simple method for determining the pro and antioxidant activities (7). ...
Background
Premature menopause (PM) is the cessation of ovarian function before age 40. PM women are more likely to have cardiovascular diseases (CVDs), diabetes, and mental disorders. This is the first study that assessed the association of single nucleotide polymorphisms (SNPs) with anti-heat shock protein 27 (Hsp27), High-sensitivity C-reactive protein (hs-CRP), and PM and serum pro-oxidant-antioxidant balance (PAB), as putative risk factors for CVDs. We aimed to explore the association of oxidative stress markers with eight different SNPs shown to be related to premature menopause.
Materials and Methods
In this cross-sectional research, we included 183 healthy women and 117 premature menopausal women. We determined baseline characteristics for all participants and measured serum hs-CRP, anti- HSP-27 antibody titer, and PAB levels using the established methods. Genotyping for eight SNPs was done using the tetra amplification refractory mutation system polymerase chain reaction (Tetra-ARMS PCR) and allele-specific oligonucleotide PCR (ASO-PCR) methods.
Results
We found a significant difference between mean serum PAB levels and the genetic variant of rs16991615 (P=0.03). ANCOVA showed a significant effect of the genotypes rs4806660 and rs10183486 on hs-CRP serum levels in the case and control groups, respectively (P=0.04 and P=0.007). ANCOVA also showed an association between rs244715 genotypes and anti-hsp27 serum levels in the case group (P=0.02). There was a significant effect of the genotypes of rs451417 on the serum hs-CRP level in the control group (P=0.03).
Conclusion
There was a significant association of the genetic variants related to PM with oxidative stress and inflammatory markers (serum PAB, anti-hsp27 antibody, and hs-CRP). Accordingly, this seems to be an effective approach to predicting susceptible subjects for cardiovascular and mental disorders as well as various cancers.
... 16) The common measurement for XOR activity is almost uric acid production. 17) Although the electron spin resonance method can selectively detect superoxide, 18) it is not widely used because of limitations in the detection equipment and the need to be skilled in waveform analysis. In this study, we measured superoxide production by chemiluminescence using L-012. ...
Xanthine oxidase (XO) produces reactive oxygen species (ROS) and has been associated with vascular endothelial dysfunction. While the effects of xanthine oxidoreductase (XOR) inhibitors on inhibiting the generation of uric acid from xanthine have been reported, much less is known about their effects on XO-induced ROS. The mechanisms of action of each XOR inhibitor vary, but it is not known whether XOR inhibitors’ effects on oxidative stress also vary. The purpose of this study is to compare the effects of different XOR inhibitors on XO-induced ROS. We used an in vitro chemiluminescence assay with clinically relevant doses of XOR inhibitors (allopurinol, oxypurinol, febuxostat, and topiroxostat) to investigate their effects on circulating XO-derived ROS. All XOR inhibitors significantly inhibited ROS production, with febuxostat and topiroxostat showing strong effects. These results confirm differences in the effects at clinical did among XOR inhibitors on XO, with topiroxostat demonstrating a strong suppression of ROS production. This study should help guide clinical practice in using XOR inhibitors to improve patient care and management.
... Both endothelial dysfunction and atherosclerosis can promote CVD, which in turn could reduce functional performance. 23 Second, participants with CKD were more likely to suffer from anaemia, hyperphosphatasaemia, acidosis and malnutrition, which might contribute to functional impairment. [24][25][26] Third, patients with CKD often suffer from vitamin D deficiency, which is associated with lower muscle strength and disability in older adults. ...
Objectives
To examine the associations of chronic kidney disease (CKD) with dynamic functional impairment among older Chinese adults.
Design
This was a prospective longitudinal study.
Setting
Data were derived from the Chinese Longitudinal Healthy Longevity Study.
Participants
All adults aged ≥60 years were potentially eligible. This study included 2970 participants.
Primary outcome measures
CKD was defined as an estimated glomerular filtration rate <60 mL/min/1.73 m ² . Functional performances included instrumental activities of daily living (IADL) and basic activities of daily living (BADL), which were measured using six daily activities, including eating, dressing, transferring, using the toilet, bathing and continence, and eight daily activities, including visiting neighbours, shopping, cooking, washing clothes, walking 1 km, lifting 5 kg, crouching and standing up three times and taking public transportation, respectively.
Results
This study included 2970 participants, including 988 (33.60%) participants with CKD. Participants with CKD had higher IADL scores than those without CKD ( β= 0.895, 95% CI: 0.761 to 1.029). Furthermore, there was a significant linear trend in the association of CKD severity with the IADL score (p<0.001). Similarly, CKD was significantly associated with higher BADL scores ( β= 0.067, 95% CI: 0.017 to 0.118). However, only participants with moderate and advanced CKD had a higher BADL score ( β= 0.088 and 0.152, 95% CI: 0.006 to 0.171 and 0.019 to 0.286, respectively).
Conclusions
CKD was associated with worse functional impairment. Furthermore, there was a significant linear trend in the association of the severity of CKD with the IADL score. However, only participants with moderate and advanced CKD had higher BADL scores.
... Furthermore, ECH alleviated DOX-induced cardiac injury by regulating GPX4 inhibition-induced ferroptosis. A growing body of evidence suggests that oxidative stress is a direct or indirect pathophysiological pathway in the HF process (26). Excess ROS production causes cellular protein, lipid, and DNA damage, and the physiological antioxidant defense system cannot eliminate it, resulting in cell necrosis and apoptosis (27). ...
Echinacoside (ECH) is a compound derived from the natural herbs Cistanche and Echinacea, which has considerable protective effects on heart failure (HF). HF is characterized by myocardial damage and abnormal ferroptosis. Glutathione peroxidase 4 (GPX4) is an important regulator of ferroptosis, which plays a role in ferroptosis-related diseases. Despite this, the therapeutic mechanisms of ECH against HF remain unknown. Therefore, the aim of the present study was to investigate the cardioprotective effect and underlying mechanisms of ECH in the treatment of doxorubicin (DOX)-induced chronic HF (CHF). Cell proliferation was assessed using a CCK-8 assay. Furthermore, cardiac cell injury and oxidative stress were determined by measuring the lactate dehydrogenase (LDH), malondialdehyde (MDA), and glutathione (GSH) levels. The levels of Fe²⁺ and lipid reactive oxygen species (ROS), and expression of the biomarkers of ferroptosis, including GPX4 and prostaglandin-endoperoxide synthase 2 (PTGS2), were measured to examine cardiomyocyte ferroptosis. Additionally, RNA interference was used to silence Gpx4. In vitro and in vivo, ECH considerably reduced the MDA and LDH levels and increased the GSH level, thereby attenuating DOX-induced cardiac injury and oxidative stress. Meanwhile, ECH treatment decreased the lipid ROS levels and PTGS2 expression while increasing GPX4 expression, thereby alleviating DOX-induced cardiomyocyte ferroptosis. Moreover, knockdown of Gpx4 inhibited the protective effects of ECH on DOX-induced accumulation of lipid ROS in cardiomyocytes. These findings indicate that ECH can reduce DOX-induced cardiac injury by inhibiting ferroptosis via GPX4, highlighting its value as a potentially valuable therapeutic target in the management of CHF.
... Hence, hyperuricemia, which is a product of xanthine oxidase activity, is seen in such patients. Noxious stimuli such as some cytokines and the sustained activation of the renin-angiotensin system in CHF patients can lead to increased xanthine oxidase activity [14]. ...
Several studies have shown that an association exists between hyperuricemia and heart failure. Despite several innovative management strategies, heart failure is a significant cause of mortality worldwide. Hyperuricemia in heart failure patients leads to poorer outcomes. Additionally, hyperuricemia can be a strong surrogate marker for increased oxidative stress in heart failure patients. This oxidative stress leads to vascular endothelial damage and is linked to worsening heart failure and subsequent mortality. Hence, the measurement of serum uric acid levels in these patients can predict the present and future risk of complications of heart failure. Despite this knowledge, serum uric acid levels are not usually followed up in heart failure patients. This systematic review aims to give additional clarity to this association. We used research from the last twenty years (2002 to 2022) obtained from databases such as PubMed, PubMed Central (PMC), Google Scholar, and Science Direct. We used the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) 2020 guidelines. We removed duplicates, screened articles on the basis of title and abstract, applied eligibility criteria, and performed quality appraisal. Eventually, 15 articles were selected for review. There were 12 observational studies, two randomized controlled trials, and one meta-analysis. Our review showed that serum uric acid elevation is associated with the severity and complications of congestive heart failure. Serum uric acid can serve as a useful surrogate marker of oxidative stress in congestive heart failure (CHF) patients. The role of xanthine oxidase inhibitors needs to be evaluated further in CHF patients.
... 28 HFrEF has a high incidence Serum albumin in elderly patients with NIDCM Li et al. 755 and prevalence in patients with NIDCM so that the production of ROS within the myocardium and vasculature will substantially increase. 6,29,30 ROS contributes to cardiac remodeling by inducing hypertrophic signaling, apoptosis, and necrosis, involved in the progression of LV dysfunction. 31,32 When abnormal production of ROS exceeds the buffering capacity of the antioxidant defense systems, oxidative stress will occur and cause endothelial dysfunction by reducing the production of nitric oxide (NO). ...
Aims:
Hypoalbuminemia was extensively used to diagnose malnutrition in older adults. Malnutrition was associated with mortality in elderly patients with cardiovascular diseases. The relationship between hypoalbuminemia and clinical outcomes in elderly patients with nonischemic dilated cardiomyopathy (NIDCM) remains unknown.
Methods:
A total of 1058 consecutive patients with NIDCM (age ≥60 years) were retrospectively enrolled from January 2010 to December 2019. Univariate and multivariate analyses were performed to assess the association of hypoalbuminemia with clinical outcomes.
Results:
Patients with hypoalbuminemia were older (69.29 ± 6.67 vs. 67.61 ± 5.90 years, P < 0.001) and had higher prevalence of in-hospital and long-term death than those without (6.9 vs. 1.7%, 50.7 vs. 35.2%, P < 0.001). Logistic regression analysis showed that hypoalbuminemia was significantly related to in-hospital death [odds ratio (OR): 4.334, 95% confidence interval (CI): 2.185-8.597, P < 0.001]. Kaplan-Meier survival analysis showed that patients with hypoalbuminemia had worse prognosis than those with nonhypoalbuminemia (log-rank χ2 28.96, P < 0.001). After adjusting for age, serum creatinine, HDL-C, AST/ALT hypoalbuminemia, LVEF and diabetes, hypoalbuminemia remained an independent predictor for long-term death (hazard ratio 1.322, 95% CI 0.046-1.670, P = 0.019).
Conclusion:
Hypoalbuminemia was associated with increased risk of in-hospital and long-term mortality in elderly patients with NIDCM.
... 25 In addition, oxidative stress is followed by an endothelial malfunction that has been visualized to be an important cause of the progression of CVD. 26 It has also been recognized that endothelial dysfunction resulting from LPS injection contributes to the pathogenesis and development of CVD. 7 LPS has been found to disturb the normal function of endothelial cells via overexpression of adhesion molecules such as vascular cell adhesion molecule 1(VCAM-1) and P-selectin. 27 In addition, LPS can enhance the generation of inflammatory cytokines and oxidative stress indicators in vessels and the heart. ...
Introduction:
Inflammation and oxidative stress are contributed to cardiovascular diseases. Vitamin D (Vit D) has antioxidant and anti-inflammatory properties. In the current research, the effect of Vit D on cardiac fibrosis and inflammation, and oxidative stress indicators in cardiovascular tissues was studied in lipopolysaccharides(LPS) injected rats.
Methods:
Rats were distributed into 5 groups and were treated for 2 weeks. Control: received vehicle(saline supplemented with tween-80) instead of Vit D and saline instead of LPS, LPS: treated by 1 mg/kg of LPS and was given vehicle instead of Vit D, LPS-Vit D groups: received 3 doses of Vit D (100, 1000, and 10000 IU/kg) of Vit D in addition to LPS. Vit D was dissolved in saline supplemented with tween-80 (final concentration 0.1%) and LPS was dissolved in saline. The white blood cell (WBC) was counted. Oxidative stress markers were determined in serum, aorta, and heart. Cardiac tissue fibrosis was also estimated using Masson's trichrome staining method.
Results:
WBC and malondialdehyde (MDA) were higher in the LPS group than the control group, whereas the thiol content, superoxide dismutase (SOD), and catalase (CAT) were lower in the LPS group than the control group (P<0.01 and P<0.001). Administration of Vit D decreased WBC (P<0.001) and MDA (P<0.05 and P<0.001) while enhanced thiol (dose 10000 IU/Kg) (P<0.001), SOD (dose 10000 IU/kg) (P<0.001), and CAT (P<0.05 and P<0.001) compared to the LPS group. All doses of Vit D also decreased cardiac fibrosis compared to the LPS group (P<0.001).
Conclusion:
Vit D protected the cardiovascular against the detrimental effect of LPS. This cardiovascular protection can be attributed to the antioxidant and anti-inflammatory properties of Vit D.
... Interestingly, accumulating evidence suggests that HDP, in particular preeclampsia, are maternal vascular disorders characterized by endothelial dysfunction and angiogenic imbalance with a life-long increased cardiovascular risk [9,10]. Hyperuricemia due to hyperactivity of xanthine oxidase produces reactive oxygen species and is associated with the development of endothelial and vascular dysfunction [2,11]. This pathogenetic mechanism may play a crucial role in the development and severity of preeclampsia [12]. ...
Objective:
Preeclampsia is one of the most severe diseases among the hypertensive disorders of pregnancy (HDP) and the leading cause of maternal and fetal morbidity and mortality. It is of crucial importance to early identify women at a high risk for preeclampsia to implement appropriate preventive strategies. In our study, we aimed to test the hypothesis that serum uric acid to creatinine ratio (SUA/sCr) is related to the development of preeclampsia and maternal and neonatal complications.
Methods:
We searched for uric acid and creatine values in the medical records of 269 women who consecutively attended our HDP Clinic from December 2018 to December 2022. We compared the baseline characteristics of participants with normotensive pregnancy (n = 57), to those with HDP without preeclampsia (HDP-non-PE) (n = 100) and those with preeclampsia (n = 112), and we performed adjusted logistic regression analysis to test the associations between SUA/sCr and the development of preeclampsia and maternal and neonatal complications.
Results:
SUA/sCr was consistently higher in women with preeclampsia in all trimesters of pregnancy. Higher SUA/sCr at the third trimester was associated with an increased odd of developing preeclampsia [odds ratio (OR) 1.29, confidence interval (CI) 1.15-1.50, P = 0.001], preterm birth (OR 1.23, CI 1.05-1.45, P = 0.011), and composite neonatal outcome (OR 1.33, CI 1.12-1.59, P = 0.001), after adjustment for age, BMI before pregnancy, nulliparity, antihypertensive therapy, and acetylsalicylic acid therapy during pregnancy.
Conclusions:
Having higher SUA/sCr during pregnancy is associated with the development of PE and adverse pregnancy outcomes. Controlled prospective studies are warranted to clarify the predictive power of this novel marker during pregnancy.
... Also, xanthine oxidase-derived ROS contributes to endothelial dysfunction. The enzyme activation has been implicated in increased vascular O 2 − generation in patients with chronic heart failure [83], coronary artery disease [72,84] and in the animal model of hypercholesterolemia [85]. It was reported that the expression and activity of xanthine oxidase in endothelial cells is upregulated by angiotensin II (Ang II) treatment [86]. ...
Nitric oxide (NO) is one of the most important molecules released by endothelial cells, and its antiatherogenic properties support cardiovascular homeostasis. Diminished NO bioavailability is a common hallmark of endothelial dysfunction underlying the pathogenesis of the cardiovascular disease. Vascular NO is synthesized by endothelial nitric oxide synthase (eNOS) from the substrate L-arginine (L-Arg), with tetrahydrobiopterin (BH4) as an essential cofactor. Cardiovascular risk factors such as diabetes, dyslipidemia, hypertension, aging, or smoking increase vascular oxidative stress that strongly affects eNOS activity and leads to eNOS uncoupling. Uncoupled eNOS produces superoxide anion (O2−) instead of NO, thus becoming a source of harmful free radicals exacerbating the oxidative stress further. eNOS uncoupling is thought to be one of the major underlying causes of endothelial dysfunction observed in the pathogenesis of vascular diseases. Here, we discuss the main mechanisms of eNOS uncoupling, including oxidative depletion of the critical eNOS cofactor BH4, deficiency of eNOS substrate L-Arg, or accumulation of its analog asymmetrical dimethylarginine (ADMA), and eNOS S-glutathionylation. Moreover, potential therapeutic approaches that prevent eNOS uncoupling by improving cofactor availability, restoration of L-Arg/ADMA ratio, or modulation of eNOS S-glutathionylation are briefly outlined.
... Patients with HF have been found to have markedly reduced endothelium-associated superoxide dismutase (SOD) activity and over 200% greater endothelium-bound XOR activity compared to controls [55]. A prospective study of patients with acute HF showed that patients in the low XOR group had significantly worse prognoses than those in the high XOR group within 365 days. ...
Xanthine oxidoreductase (XOR) and its products contribute to the development of chronic inflammation and oxidative stress. Excessive XOR activity is believed to promote inflammatory responses and atherosclerotic plaque formation, which are major cardiovascular risk factors. The mechanisms of XOR activity in the development and progression of cardiovascular disease (CVD), coupled with the complexity of the relationship between XOR activity and the biological effects of uric acid; reactive oxygen species; and nitric oxide, which are the major products of XOR activity, have long been debated, but have not yet been clearly elucidated. Recently, a system for measuring highly sensitive XOR activity in human plasma was established, and there has been progress in the research on the mechanisms of XOR activity. In addition, there are accumulating findings about the relationship between XOR activity and CVD. In this narrative review, we summarize existing knowledge regarding plasma XOR activity and its relationship with CVD and discuss future perspectives.
... An American study showed that uric acid inhibits the transport of amino acids in the placental system, leading to intrauterine growth restriction (Bainbridge et al. 2009b). As XO mediates uric acid production and produces reactive oxygen species (Landmesser et al. 2002), SUC may partly reflect the increase in oxidative stress. Other studies have also shown that uric acid can stimulate the basal expression of cyclooxygenase 2 both in vitro and in vivo, suggesting that inflammatory mechanisms may participate in the process of foetal growth restriction (Kanellis et al. 2003, Ohtsubo et al. 2004. ...
In high-altitude regions, low birth weight is mainly caused by hypoxia. We aimed to determine whether maternal serum uric acid (SUC) level was associated with decreased foetal birth weight. The relevant data of individual pregnant women who delivered between 37 and 40 weeks in the People’s Hospital of Naqu City, Tibet were retrospectively collected. The correlation between maternal SUC and birth weight was examined using multivariate linear regression analysis and subgroup analysis. The results showed that there was a significant negative correlation between SUC and birth weight in pregnant women with proteinuria, female foetuses, and primiparas. Fitting smoothing curve analysis showed that there was a negative linear correlation between SUC and birth weight in primiparas and female foetuses. Maternal SUC is negatively associated with foetal birth weight in a single pregnancy with proteinuria, primipara, or female foetuses in the Naqu region of Tibet, China.
IMPACT STATEMENT
What is already known on this subject? Preeclampsia associated with hyperuricaemia can affect foetal birth weight, foetal birth weight in plains area is negatively correlated with maternal hyperuricaemia.
What do the results of this study add? Maternal SUC was negatively correlated with foetal birth weight, especially in primipara, mothers with proteinuria, and pregnant girls.
What are the implications of these findings for clinical practice and/or further research? The results suggest that attention should be paid to SUC in pregnant women, especially in primipara, mothers with proteinuria, and pregnant girls, in the prevention of low birth weight infants in Naqu Plateau area of Tibet.
... Second, AKT1, HSPB1 and NOS3 are positively correlated based on our results (see Additional le 7), indicating they may exert a synergetic effect on cardiac dysfunction. Third, the NOS3-HSP90-AKT complex responds to oxidative stress, cell redox homeostasis, negative regulation of oxidative stress-induced cell death and detoxi cation of reactive oxygen species, which is consistent with earlier researches [34][35][36][37]. Finally, AKT1, HSPB1 and NOS3 were positively associated with natural killer cells and Th17 in ltration. ...
Background
Oxidative stress and immune cells infiltration have been shown to play a role in chronic heart failure (CHF). In this study, we aimed to explore oxidative stress status and immune cells infiltration associated with CHF and they may identify new candidates for biomarker.
Methods
CHF samples were collected from Gene Expression Omnibus (GEO) database (GSE5406, GSE9128, and GSE76701). Differentially expressed genes of oxidative stress (OSDEGs) were identified based on differentially expressed genes (DEGs) and oxidative stress gene set. Multiple machine learning methods were adopted to screen signature OSDEGs. Consensus clustering was used to divide samples into categories with different OSDEGs levels. Functional enrichment analysis was conducted to evaluate the gene enrichment signaling pathways in OSDEGs. The correlation between OSDEGs and immune cells infiltration was performed by single sample gene set enrichment analysis (ssGSEA) and CIBERSORT.
Results
Overall, 33 differentially expressed oxidative stress-related genes were identified. Among them, 10 were further regarded as independent predictors for CHF, and used to develop a nomogram that had shown good performance in predicting CHF with an area under the receiver operating characteristic curve of 0.93(95%CI: 0.85-1.00) in the training sets and 0.81 (95%CI: 0.43-1.00) in the validation set. Furthermore, hub genes were mainly enriched in the detoxification of reactive oxygen species pathway, cell redox homeostasis and negative regulation of oxidative stress-induced cell death. The CHF and control samples showed significantly different distributions (P < 0.05) of monocytes and M0 macrophages. In addition, both AKT1 and NOS3 held a positive relationship with monocytes, but HSP90AA1 was negatively correlated with natural killer cells and type 1 T helper cells, respectively.
Conclusions
These results indicate that oxidative stress status is closely linked to CHF risk prediction and immune cell infiltration. Thus, the oxidative stress-based molecular signature may be target for CHF intervention.
... Peroxynitrite plays a key role in oxidation of LDL and as proatherogenic [8]. In addition, peroxynitrite leads to the degradation of the eNOS cofactor tetrahydrobiopterin (BH4), resulting in an uncoupling of eNOS [9]. An excess of oxidant also leads to a reduction of BH4 with an increase in BH2. ...
Peroxisome function has long been associated with oxygen metabolism. High concentrations of hydrogen peroxide (H2O2−) producing oxidases are in the set of peroxisomes and their antioxidant enzymes, especially catalase. Reactive oxygen species (ROS) can certainly be considered as an intracellular multifunctional biological factor which are released and scevenged in peroxisomes. They are known to be involved in normal cellular functions such as signaling mediators, overproduction under oxidative stress conditions leading to adverse cellular effects, cell death, and various other pathological conditions. This review provides an insight into the relationship between peroxisomes and ROS, which are emerging as key players in the dynamic rotation of ROS metabolism and oxidative damage. Various conditions upset the balance between ROS production and removal in peroxisomes. The current review also targets the ROS-inhibiting enzymes and exemplifying the effects of antioxidants in pre-clinical and clinical evaluation of natural and herbal supplements.
... To detect how markers in the blood can correlate with oxidative-damaged mitochondria in the heart, we selected circulating endothelial cells (CECs) as the target of our study. Meanwhile, cardiac microvascular endothelial cells (CMECs) are among the most abundant cells in the heart and actively participate in cardiac physiology and pathology [27,28]. Under some pathological conditions, such as atherosclerosis, CMECs in the heart detach from the basement membrane, resulting in increased numbers of CECs within the blood, making CECs an ideal tissue to assess cell damage in the heart from blood [13,29]. ...
Objective:
This study is aimed at identifying the potential diagnostic markers for circulating endothelial cells (CECs) for acute myocardial ischemia (AMI) and exploring the regulatory mechanisms of the selected biomarker in mitochondrial oxidative damage and vascular inflammation in AMI pathology.
Methods:
Utilizing the Gene Expression Omnibus dataset GSE66360, we scanned for differentially expressed genes (DEGs) in 49 AMI patients and 50 healthy subjects. To discover possible biomarkers, LASSO regression and support vector machine recursive feature elimination examinations were conducted. Using the GSE60993 and GSE123342 datasets and AMI rat models, the expression levels and diagnostic accuracy of the biomarkers in AMI were thoroughly verified. CIBERSORT was employed to evaluate the compositional patterns of 22 distinct immunological cell percentages in AMI according to combined cohorts. The oxidative-damaged mitochondria were detected by confocal microscopy observation of MitoTracker, ROS-DCFH-DA, and mCherry-GFP-LC3B.
Results:
In total, 122 genes were identified. The identified DEGs primarily contributed in arteriosclerosis, arteriosclerotic cardiovascular disorders, bacterial infectious disorder, coronary artery disease, and myocardial infarction. Nine features (NR4A2, GABARAPL1 (GEC1), CLEC4D, ITLN1, SNORD89, ZFP36, CH25H, CCR2, and EFEMP1) of the DEGs were shared by two algorithms, and GABARAPL1 (GEC1) was identified and verified as a diagnostic mitochondrial biomarker for AMI. Confocal results showed that there existed mitochondrial damage and oxidative stress in cardiac CMECs after AMI, and the blocked autophagy flux could be released by exosome burst in cardiac CMECs and blood CECs. Immune cell infiltration testing declared that elevated GEC1 expression in blood CECs was linked to the rise of monocytes and neutrophils. Functional tests revealed that high GEC1 expression in CMECs and CECs could activate the vascular inflammatory response by stimulating NLRP3 inflammasome production after AMI.
Conclusion:
Oxidative-damaged mitochondria in cardiac CMECs activate GEC1-mediated autophagosomes but block autophagy flux after AMI. The exfoliated cardiac CMECs evolve into abnormal blood CECs, and the undegraded GEC1 autophagosomes produce a large number of NLRP3 inflammasomes by exosome burst, stimulating the increase in monocytes and neutrophils and ultimately triggering vascular inflammation after AMI. Therefore, GEC1 in blood CECs is a highly specific diagnostic mitochondrial biomarker for AMI.
... Uric acid level has been reported closely related to cardiac diseases, which enhances oxidative stress, disrupts cardiovascular function, promotes inflammations, increases insulin resistance, and activates the RAAS [51][52][53][54][55][56]. Although not entirely clear, the mechanism pathogenesis of AF can be summarized as atrial fibrosis, inflammations, oxidative stress, and dysfunction of RAAS [57][58][59][60], almost parallel to mechanisms mentioned previously. ...
Association between hyperuricemia (HUA) and atrial fibrillation (AF) remains unclear. We reviewed clinical evidence and aimed to determine whether hyperuricemia leads to a high risk of atrial fibrillation. Most studies were identified through databases online. Keywords used in literature search were hyperuricemia, atrial fibrillation, metabolic disorder, endocrine disorder, or uric acid. Three studies were provided by the authors. Literature search was performed without any data or language restriction. Observational studies, including cohort studies and cross-sectional studies, were used. Study type should be clearly defined. Cross-sectional studies should clearly introduce the sources of epidemiological data. Studies were excluded if with too many complications unrelated to AF enrolled. Data were independently extracted by three individuals. Data synthesis was conducted by R version 4.1.2. Prevalence of atrial fibrillation was the main outcome. Results of meta-analysis were presented as risk ratio (RR) for different prevalence of AF between individuals with and without HUA. All data included were obtained after follow-up work is completed. Data from 608,810 participants showed that patients with hyperuricemia were easier to suffer from atrial fibrillation (RR, 2.42; 95% CI, 1.24–3.03). And the meta-regressions suggested growth of linear proportion between the ratio of current drinkers and hyperuricemia (QM = 41.0069, P < 0.001 ). Subgroup analyses demonstrated consistent results in different countries. And design of the observational studies brought heterogeneity, but no uncertainties. Patients with hyperuricemia were easier to suffer from atrial fibrillation. Treatment of hyperuricemia or gout may bring potential benefits for AF patients.
... Superoxide dismutase (SOD) is responsible for the inactivation of ROS in cardiomyocytes. Previous studies have found that SOD plays an important role in the development of HF in animal model (12)(13)(14) and clinical practice (5). To our knowledge, although a study has recently shown that SOD is a potential link between left ventricular structure remodeling and the development of subsequent HF in patients with cardiovascular disease (15), the relationship between SOD and LVEF has not been evaluated in the patients with diabetes and ACS. ...
Background: Superoxide dismutase (SOD) and inflammatory markers are reported to have association with cardiovascular disease. However, no previous study has assessed the value of SOD and inflammatory markers as predictive indicator of heart failure in patients with diabetes and acute coronary syndrome (ACS) in the same study.
Objective: The objective of this study is to compare the predictive implications of SOD activity, C-reactive protein (CRP) and fibrinogen for reduced left ventricular ejection fraction (LVEF) in patients with diabetes and ACS.
Method: The study included 2377 inpatients with type 2 diabetes who had an ACS admitted to the Shandong Provincial Hospital affiliated to Shandong First Medical University from January 2016 to January 2021.
Result: Despite taking the lowest quartile as reference (OR 0.368, 95% CI 0.493–0.825, P = 0.001) or examining 1 normalized unit increase (OR 0.651, 95% CI 0.482–0.880, P = 0.005), the SOD activity was exhibited to be the strongest predictive indicator of reduced LVEF, independent of confounding factors. The SOD activity showed the most powerful predictor value for reduced LVEF with the highest area under the receiver operating characteristic curve of 0.658.
Conclusions: SOD activity is a stronger predictor of reduced LVEF than CRP and fibrinogen in patients with diabetes and ACS.
... The final product UA is a non-specific marker for oxidative stress. Excessive activation of XO induces hyperuricemia, and XO activity is upregulated in patients with HF [15]. XO inhibitors are used for treating hyperuricemia and have been shown to improve myocardial energetic efficiency. ...
Hyperuricemia (HU) is important and common comorbidity that often coexist in patients with heart failure (HF). High values of serum uric acid are associated to severe heart failure. The purpose of the present study was to evaluate a UA-lowering and prognostic effects of allopurinol in patients with chronic HF and hyperuricemia.We studied 75 patients with HF and increased UA levels, who have been admitted to hospital. All patients aged 18 years and older were eligible, provided a left ventricular ejection fraction of 45% or less was documented on echocardiography during the enrolment visit and signs and symptoms of chronic heart failure were present. Patient baseline assessment included a standardized HF history regarding HF aetiology (classified as ischemic or non-ischemic) and co-morbidities. All patients underwent a standardized clinical evaluation, including physical examination, determination of NYHA class, determination of body weight. Blood samples were drawn from an antecubital vein in the morning for the assessment of a full blood count and clinical chemistry. Patients were divided in to two groups: 50 patients (group 1) received allopurinol. The initial dose of in most patients was 200 mg/day and it was reduced according to their renal function or UA level. 25 patients (group 2) – controlled group. Treatment duration was 6 months.Repeated studies after 3 months showed the following results: Uric acid treatment improved the echocardiographic parameters (LVEF, LV mass index, IVS, PW, stroke volume), reduced NT- proBNP, improved renal function, Improved NYHA functional class;6-minute walking test distance improved significantly in the UA- treatment group and quality of life. The QoL parameters that was improved included reduced physical limitation, improved mobility, selfcare, increased daily activities and reduced discomfort, anxiety and depression.Among patients with HF and elevated serum uric acid levels, allopurinol use was safe and strongly associated with improved outcomes.
... Almost all types of CVD were associated with hypertension, diabetes, smoking and high cholesterol. These CVFs can contribute to endothelial dysfunction [38][39][40][41][42][43][44][45][46][47][48]. High homocysteine and ADMA values also showed a negative effect on EPC count [49,50]. ...
Endothelial progenitor cells (EPC) may influence the integrity and stability of the vascular endothelium. The association of an altered total EPC number and function with cardiovascular diseases (CVD) and risk factors (CVF) was discussed; however, their role and applicability as biomarkers for clinical purposes have not yet been defined. Endothelial dysfunction is one of the key mechanisms in CVD. The assessment of endothelial dysfunction in vivo remains a major challenge, especially for a clinical evaluation of the need for therapeutic interventions or for primary prevention of CVD. One of the main challenges is the heterogeneity of this particular cell population. Endothelial cells (EC) can become senescent, and the majority of circulating endothelial cells (CEC) show evidence of apoptosis or necrosis. There are a few viable CECs that have properties similar to those of an endothelial progenitor cell. To use EPC levels as a biomarker for vascular function and cumulative cardiovascular risk, a correct definition of their phenotype, as well as an update on the clinical application and practicability of current isolation methods, are an urgent priority.
... In HF, this mechanism is limited, which could be seen as a protective mechanism aiming to preserve a minimal degree of perfusion levels for the brain, heart, and respiratory muscles (Poole et al., 2012). It is likely mediated by overactivation of the sympathetic system (a typical feature of advanced HF) (Joyner et al., 1992) combined with diminished capacity for metabolic vasodilatation (due to oxidative stress and endothelial dysfunction) (Landmesser et al., 2002;Sharma and Davidoff, 2002) leading to elevated peripheral vascular resistance (PVR). The link between PVR and tonic activation of PChRs in HF was evaluated by Tubek et al. . ...
Peripheral chemoreceptors (PChRs), because of their strategic localization at the bifurcation of the common carotid artery and along the aortic arch, play an important protective role against hypoxia. Stimulation of PChRs evokes hyperventilation and hypertension to maintain adequate oxygenation of critical organs. A relationship between increased sensitivity of PChRs (hyperreflexia) and exercise intolerance (ExIn) in patients with heart failure (HF) has been previously reported. Moreover, some studies employing an acute blockade of PChRs (e.g., using oxygen or opioids) demonstrated improvement in exercise capacity, suggesting that hypertonicity is also involved in the development of ExIn in HF. Nonetheless, the precise mechanisms linking dysfunctional PChRs to ExIn remain unclear. From the clinical perspective, there are two main factors limiting exercise capacity in HF patients: subjective perception of dyspnoea and muscle fatigue. Both have many determinants that might be influenced by abnormal signalling from PChRs, including: exertional hyperventilation, oscillatory ventilation, ergoreceptor oversensitivity, and augmented sympathetic tone. The latter results in reduced muscle perfusion and altered muscle structure. In this review, we intend to present the milieu of abnormalities tied to malfunctioning PChRs and discuss their role in the complex relationships leading, ultimately, to ExIn.
... In part, they can result from the autoxidation of catecholamines and proinflammatory cytokine release. 1,3,4 ROS are highly involved in redox signaling in heart tissue. Under physiological conditions, cardiac ROS signaling regulates cardiomyocyte maturation, heart development, excitation-contraction coupling, cardiac calcium handling, and vascular tone. ...
Acute myocardial infarction (MI) is the leading cause of mortality worldwide with premenopausal women showing a lower incidence of cardiovascular disease compared to men of the same age. After menopause, this advantage disappears, suggesting that sex hormones play a cardioprotective role. The study was aimed to assess on the activity of antioxidant enzymes in plasma and the respiratory function of isolated heart mitochondria after induction of MI in rats after ovariectomy and oestradiol benzoate supplementation. Sprague-Dawley female rats were ovariectomized 3 months prior to the induction of MI, and supplemented/not supplemented with oestrogen 3 months before/7 days after induction of MI. No significant differences in glutathione peroxidase activities were found in any group. Differences between values were only significant in the ovariectomized not supplemented group (p <0.01) for the glutathione reductase activity and glutathione concentrations. In isolated mitochondria (7 days after MI), the decline in respiration was observed comparing the ovariectomized and non-ovariectomized group. Respiratory functions did not show significant differences between animals supplemented with oestrogen before MI or treated with oestrogen after MI. Ovariectomy worsened mitochondrial dysfunction after MI, and oestrogen supplementation before or after induction of MI did not improve mitochondrial function.
... The final product UA is a non-specific marker for oxidative stress. Excessive activation of XO induces hyperuricemia, and XO activity is upregulated in patients with HF. 10 Furthermore, a high UA level has been reported to be a strong and independent marker for impaired prognosis in patients with HF and acute myocardial infarction. [11][12][13] XO inhibitors are used for treating hyperuricemia and have been shown to improve myocardial energetic efficiency, left ventricular ejection fraction (LVEF), and plasma B-type natriuretic peptide (BNP) levels in patients with HF. [14][15][16] However, a previous double-blind, multicenter randomized placebo-controlled trial did not reveal improvements after allopurinol administration in clinical status, quality of life, or LVEF in high-risk patients with HF with reduced LVEF and hyperuricemia. ...
Objective
Heart failure (HF) is a common and highly morbid cardiovascular disorder. Oxidative stress worsens HF, and uric acid (UA) is a useful oxidative stress marker. The novel anti-hyperuricemic drug febuxostat is a potent non-purine selective xanthine oxidase inhibitor. The present study examined the UA-lowering and prognostic effects of febuxostat in patients with HF compared with conventional allopurinol.
Methods
This multicenter, randomized trial included 263 patients with chronic HF who were randomly assigned to two groups and received allopurinol or febuxostat (UA >7.0 mg/dL). All patients were followed up for 3 years after enrollment.
Results
There were no significant differences in baseline clinical characteristics between the two groups. The UA level was significantly decreased after 3 years of drug administration compared with the baseline in both groups. Urine levels of the oxidative stress marker 8-hydroxy-2′-deoxyguanosine were lower in the febuxostat group than in the allopurinol group (11.0 ± 9.6 vs. 22.9 ± 15.9 ng/mL), and the rate of patients free from hospitalization due to worsening HF tended to be higher in the febuxostat group than in the allopurinol group (89.0% vs. 83.0%).
Conclusions
Febuxostat is potentially more effective than allopurinol for treating patients with chronic HF and hyperuricemia. This study was registered in the University Hospital Medical Information Network Clinical Trials Registry ( https://www.umin.ac.jp/ctr/ ; ID: 000009817).
... They are several enzyme systems that can generate ROS in the vascular wall. Among the ROS-producing enzymes, four of them seem to play a crucial role, namely, a dysfunctional endothelial NO synthase, enzymes of the mitochondrial respiratory chain, XO, and NADPH oxidase (Landmesser et al. 2002;George and Struthers 2009;Faria et al. 2018;Daiber et al. 2019;Ding et al. 2019;Mazat et al. 2020). Notably, NADPH oxidase can induce eNOS uncoupling as well as XO activation (Landmesser et al. 2007). ...
Research evidence has indicated that increasing numbers of elderly are suffering from age-related diseases such as neurodegenerative disease, atherosclerosis, cancer, diabetes, and osteoporosis. These diseases are characterized by progressive loss of tissue and organ function. Substantial evidence has revealed that the overproduction of ROS may play a crucial role in the development of these diseases. Oxidative stress is regarded as an imbalance between antioxidant and prooxidant species and thus leads to cellular and molecular damage. ROS are produced within the biological system to mediate cellular processes, for instance, stressor response, inflammation, and cell survival. The elderly are vulnerable to oxidative stress due to a reduction in the efficiency of the endogenous antioxidant system. Despite ROS production may not be an essential factor for aging, they are more likely to aggravate age-related diseases development through interaction with mitochondria and oxidative damage. The exact molecular mode of actions of aging and age-related diseases linked to the disturbance of redox balance remains unclear. In this chapter, we discussed the role of inflammation in the pathological mechanisms of obesity, neurodegenerative disease, atherosclerosis, cancer, diabetes, and osteoporosis.
... 2 In patients with heart failure, the uptake of XO in local tissues is enhanced, leading to increased ROS production. 3 However, previous studies failed to find oxidative stress-related non-invasive prognostic markers. ...
Background:The prognostic impact of urinary isoxanthopterin (U-IXP), a recently proposed marker of oxidative stress, in patients with heart failure remains unknown.
Methods and Results:Patients who were admitted to our institute for decompensated heart failure were prospectively included in the study; U-IXP was measured on admission. The association between the U-IXP concentration and a composite primary outcome that included cardiovascular death and heart failure readmissions following the index discharge was investigated. In all, 42 patients (median age 78 years [interquartile range {IQR} 69–85 years]; 25 males) were included in the study. The median U-IXP concentration on admission was 0.58 μmol/g creatinine (Cre; IQR 0.35–0.95 μmol/g Cre). A higher U-IXP concentration was an independent predictor of the primary outcome adjusted for clinical potential confounders and was associated with a significantly higher cumulative incidence of the primary outcome (71% vs. 16%, P=0.001) at a cut-off of 0.93 μmol/g Cre.
Conclusions:U-IXP on admission was associated with cardiovascular death or heart failure readmission following the index discharge in patients with decompensated heart failure. The clinical implication of aggressive interventions to normalize U-IXP and the detailed prognostic mechanism of U-IXP in heart failure patients remain the next concerns.
... Endothelial barrier function is dynamically regulated by secondary messengers such as cyclic adenosine monophosphate (cAMP). Evidence suggests that EnDF is an early key step in the development, progression, and manifestation of atherosclerosis (Davignon and Ganz 2004), in chronic renal failure (Yildiz et al. 2003), congestive heart failure (Landmesser et al. 2002), coronary artery disease (Monnink et al. 2002), and type 1 (Beckman et al. 2003) and type 2 diabetes (Endemann et al. 2004). and in the metabolic syndrome such as dyslipidemia (Engler et al. 2003) also associated with obesity (Raitakari et al. 2004), hyperhomocysteinemia (Virdis et al. 2001), and smoking (Oida et al. 2003), in the absence of cardiovascular disease. ...
Arsenic exposure to the population leads to serious health problems like neurotoxicity, nephrotoxicity, and cardiovascular abnormality. In the present study, the work has been commenced to discover the prospect of rolipram a phosphodiestrase-4 (PDE-4) inhibitor against sodium arsenite (SA)–induced vascular endothelial dysfunction (EnDF) leading to dementia in rats. Wistar rats were treated with SA (5 mg/kg body weight/day orally) for 44 days for induction of vascular EnDF and dementia. Learning and memory were evaluated using Morris water maze (MWM) test. Vascular EnDF was evaluated using aortic ring preparation. Various biochemical parameters were also evaluated like brain oxidative stress (viz. reduced glutathione and thiobarbituric acid reactive substances level), serum nitrite/nitrate activity, acetylcholinesterase activity, and inflammatory markers (viz. neutrophil infiltration in brain and myeloperoxidase). SA-treated rats showed poor performance in water maze trials indicating attenuated memory and ability to learn with significant rise (p < 0.05) in brain acetylcholinesterase activity, brain oxidative stress, neutrophil count, and significant decrease (p < 0.05) in serum nitrite/nitrate levels and vascular endothelial functions. Rolipram (PDE-4 inhibitor) treatment (0.03 mg/kg and 0.06 mg/kg body weight, intraperitoneally daily for 14 days) significantly improved memory and learning abilities, and restored various biochemical parameters and EnDF. It is concluded that PDE-4 modulator may be considered the prospective target for the treatment of SA-induced vascular EnDF and related dementia.
... Hence, the marked decrease in AI in a concentration-dependent manner in the treated rats reveals the anti-hyperlipidemic role of FA-biscuit diet in hypertensive rats as represented in (Landmesser et al. 2002). The activities of CAT and SOD in the heart and lungs were significantly reduced in LL-NAME hypertensive rats which could be as a result of the excessive burden from free radicals or reactive oxygen species (ROS) generated (Figures 6 and 7). ...
Dietary sources of functional foods and nutraceutical have shown strong potentials in the management of hypertension and its complications. Sandpaper leaves, Ficus asper-ifolia Miq (FA), particularly found in Africa has a rich folkloric history in the management of diabetes and hypertension. This study produced biscuits supplemented with blends of FA at 2.5% and 5% fed to N w (G)-nitro-L-arginine-methyl-ester (L-NAME, 40 mg/kg/day) induced-hypertensive rats for 14 days followed by the assessment of blood pressure, lipid profile, and atherogenic index in hypertensive rats. The phenolic constituents of FA blends were analyzed using high-performance liquid chromatography diode-anode (HPLC-DAD). Thereafter, the mean arterial blood pressure (MABP) and systolic blood pressure (SBP) was measured using the tail-cuff method after which the heart and lungs of rats were collected, weighed, and the antioxidant status and lipid cholesterol profile were assessed. We realized that recorded phenolic constituents in extracts of FA was at a high level and FA enriched biscuit-diet caused a significant decrease in SBP and MABP in L-NAME-induced hypertensive rats, body weight, atherogenic index and cholesterol profile in treated rats. However, FA enriched biscuit resulted in increased activities of catalase (CAT), superoxide dismutase (SOD), and glutathione-S-transferase (GST) antioxidant enzymes in the heart and lungs of hyper-tensive rats. This study revealed that FA enriched biscuit-diet does not only have anti-hypertensive and antioxidant potential in L-NAME-induced hypertensive rats but also plays a protective role in the management of hyperlipidemia.
... Differences in the WBS deletion affect the copy number for Ncf1, ultimately affecting hypertension risk and the severity of vascular stiffness [9,71]. Studies performed in Ncf1 knock-out mice revealed that p47phox has a major influence on Ang II [72] and that Ang-IImediated oxidative stress in the vasculature may be the mechanism behind the protective effect in patients whose deletion includes a copy of Ncf1 [71,73,74]. Campuzano et al. demonstrated in a mouse model that the use of therapies with Ang II type 1 receptor blocker, losartan, or NOX inhibitor apocynin were effective in reducing the risk of hypertension [73]. ...
Oxidative stress is the result of an imbalance in the redox state in a cell or a tissue. When the production of free radicals, which are physiologically essential for signaling, exceeds the antioxidant capability, pathological outcomes including oxidative damage to macromolecules, aberrant signaling, and inflammation can occur. Down syndrome (DS) and Williams-Beuren syndrome (WBS) are well-known and common genetic conditions with multi-systemic involvement. Their etiology is linked to oxidative stress with important causative genes, such as SOD-1 and NCF-1, respectively, of the diseases being primarily involved in the regulation of the redox state. Early aging, dementia, autoimmunity, and chronic inflammation are some of the main characteristics of these conditions that can be associated with oxidative stress. In recent decades, there has been a growing interest in the possible role of oxidative stress and inflammation in the pathology of these conditions. However, at present, few studies have investigated these correlations. We provide an overview of the current literature concerning the role of oxidative stress and oxidative damage in genetic syndromes with a focus on Down syndrome and WBS. We hope to provide new insights to improve the management of complications related to these diseases.
Arachidonic acid (AA) has three main metabolic pathways: the cycloxygenases (COXs) pathway, the lipoxygenases (LOXs) pathway, and the cytochrome P450s (CYPs) pathway. AA produces epoxyeicosatrienoic acids (EETs) through the CYPs pathway. EETs are very unstable in vivo and can be degraded in seconds to minutes. EETs have multiple degradation pathways, but are mainly degraded in the presence of soluble epoxide hydrolase (sEH). sEH is an enzyme of bifunctional nature, and current research focuses on the activity of its C-terminal epoxide hydrolase (sEH-H), which hydrolyzes the EETs to the corresponding inactive or low activity diol. Previous studies have reported that EETs have cardiovascular protective effects, and the activity of sEH-H plays a role by degrading EETs and inhibiting their protective effects. The activity of sEH-H plays a different role in different cells, such as inhibiting endothelial cell proliferation and migration, but promoting vascular smooth muscle cell proliferation and migration. Therefore, it is of interest whether the activity of sEH-H is involved in the initiation and progression of cardiovascular diseases by affecting the function of different cells through EETs.
Hyperuricemia (H-SUA) is widely represented in the general population and can contribute to high blood pressure and its complications. H-SUA has also a negative prognostic effect in patients with heart failure with reduced (HFrEF) and preserved ejection fraction (HFrEF). The negative effects of H-SUA involve patients with acute and chronic HF and are not related to decline in GFR and renal disease. The negative impact of H-SUA in hypertension and HF is proportional to the levels of SUA and to xanthine oxidase (XO) activity and persists after adjustment for GFR, diuretic treatment, HF functional class, and many other confounding variables. The reduction of UA levels by XO inhibitors has resulted in promising results that warrant further investigations and a better selection of involved patients. A decrease in serum UA levels has also been recently reported in patients treated with SGLT-2 inhibitors, ARNI and Vericiguat and can contribute to the clinical benefit observed with these drugs in patients with heart failure (HFrEF and HFpEF). H-SUA should be systematically considered in patients at risk of cardiovascular disease as well as in those with HF. A decrease in serum uric acid can significantly contribute to the improvement of cardiovascular outcome observed in recent randomized clinical trials.
Preserving vascular function is crucial for preventing multiorgan failure and death in ischemic and low-pressure states such as trauma/hemorrhagic shock (T/HS). It has recently been reported that inhibiting circulating proteases released from the bowel to the circulation during T/HS may preserve vascular function and improve outcomes following T/HS. This study aimed to evaluate the role of the serine protease inhibitor gabexate mesilate (GM) in preserving vascular function during T/HS when given enterally. We studied the vascular reactivity of mesenteric arteries from male Wistar rats treated with enteral GM (10 mg/kg) (GM-treated, n = 6) or control (Shock-control, n = 6) following (T/HS) using pressure myography. Concentration–response curves of endothelial-dependent and endothelial-independent agonists (e.g., acetylcholine, sodium nitroprusside) ranging from 10⁻¹⁰ to 10⁻⁵ M were performed. In a second set of experiments, ex-vivo arteries from healthy rats were perfused with plasma from shocked animals from both groups and vascular performance was similarly measured. Arteries from the GM-treated group demonstrated a preserved concentration–response curve to the α1 adrenergic agonist phenylephrine compared to arteries from Shock-control animals (− logEC50: − 5.73 ± 0.25 vs. − 6.48 ± 0.2, Shock-control vs. GM-treated, p = 0.04). When perfused with plasma from GM-treated rats, healthy arteries exhibited an even greater constriction and sensitivity to phenylephrine (− logEC50: − 6.62 ± 0.21 vs. − 7.13 ± 0.21, Shock-control vs. GM-treated, p = 0.02). Enteral GM also preserved the endothelium-dependent vascular response to agonists following T/HS and limited syndecan-1 shedding as a marker of glycocalyx compromise (41.84 ± 9 vs. 17.63 ± 3.97 ng/mL, Shock-control vs. GM-treated, p = 0.02). Syndecan-1 cleavage was correlated with plasma trypsin-like activity (r² = 0.9611). Enteral gabexate mesilate was able to maintain vascular function in experimental T/HS, which was reflected by improved hemodynamics (mean arterial pressure 50.39 ± 7.91 vs. 64.95 ± 3.43 mmHg, Shock-control vs. GM treated, p = 0.0001). Enteral serine protease inhibition may be a potential therapeutic intervention in the treatment of T/HS.
Aims:
Vascular dysfunction and elevated circulating dipeptidyl peptidase 4 (DPP4) activity are both reported to be involved in the progression of heart failure (HF). While the cardiac benefits of DPP4 inhibitors (DPP4i) have been extensively studied, little is known about the effects of DPP4i on vascular dysfunction in nondiabetic HF. This study tested the hypothesis that vildagliptin (DPP4i) mitigates aortic hyperreactivity in male HF rats.
Materials and methods:
Male Wistar rats were subjected to left ventricle (LV) radiofrequency ablation to HF induction or sham operation (SO). Six weeks after surgery, radiofrequency-ablated rats who developed HF were treated with vildagliptin (120 mg⸱kg-1⸱day-1) or vehicle for 4 weeks. Thoracic aorta reactivity, dihydroethidium fluorescence, immunoblotting experiments, and enzyme-linked immunosorbent assays were performed.
Key findings:
DPP4i ameliorated the hypercontractility of HF aortas to the α-adrenoceptor agonist phenylephrine towards SO levels. In HF, the reduced endothelium and nitric oxide (NO) anticontractile effect on phenylephrine response was restored by DPP4i. At the molecular level, this vasoprotective effect of DPP4i was accompanied by (i) reduced oxidative stress and NADPH oxidase 2 (Nox2) expression, (ii) enhanced total endothelial nitric oxide synthase (eNOS) expression and phosphorylation at Ser1177, and (iii) increased PKA activation, which acts upstream of eNOS. Additionally, DPP4i restored the higher serum angiotensin II concentration towards SO.
Significance:
Our data demonstrate that DPP4i ameliorates aortic hypercontractility, most likely by enhancing NO bioavailability, showing that the DPP4i-induced cardioprotection in male HF may arise from effects not only in the heart but also in conductance arteries.
Xanthine oxidase (XO) mediates vascular function. Chronic stress impairs cerebrovascular function and increases the risk of stroke and cognitive decline. Our study determined the role of XO on stress-induced cerebrovascular dysfunction and cognitive decline. We measured middle cerebral artery (MCA) function, free radical formation, and working memory in 6-month-old C57BL/6 mice who underwent 8 weeks of control conditions or unpredictable chronic mild stress (UCMS) with or without febuxostat (50 mg/L), a XO inhibitor. UCMS mice had an impaired MCA dilation to acetylcholine vs. controls (p < 0.0001), and increased total free radical formation, XOR protein levels, and hydrogen peroxide production in the liver compared to controls. UCMS increased hydrogen peroxide production in the brain and cerebrovasculature compared to controls. Working memory, using the y-maze test, was impaired (p < 0.05) in UCMS mice compared to control mice. However, blocking XO using febuxostat prevented the UCMS-induced impaired MCA response, while free radical production and hydrogen peroxide levels were similar to controls in the liver and brain of UCMS mice treated with febuxostat. Further, UCMS + Feb mice did not have a significant reduction in working memory. These data suggest that the cerebrovascular dysfunction associated with chronic stress may be driven by XO, which leads to a reduction in working memory.
Sodium-glucose cotransporter 2 inhibitors (SGLT2is) reduce the risk of heart failure progression and mortality rates. Moreover, osmotic diuresis induced by SGLT2 inhibition may result in an improved heart failure prognosis. Independent of conventional diuretics in patients with type 2 diabetes (T2D) and chronic heart failure, especially in patients with heart failure with preserved ejection fraction (HFpEF), it is unclear whether SGLT2i chronically reduces estimated plasma volume (ePV). As a subanalysis of the CANDLE trial, which assessed the effect of canagliflozin on N-terminal pro-brain natriuretic peptide (NT-proBNP), we examined the change (%) in ePV over 24 weeks of treatment based on the baseline level associated with diuretic usage. In the CANDLE trial, nearly all patients were clinically stable (NYHA class I–II), with approximately 70% of participants presenting a baseline phenotype of HFpEF. A total of 99 (42.5%) patients were taking diuretics (mostly furosemide) at baseline, while 134 (57.5%) were not. Relative to glimepiride, canagliflozin significantly reduced ePV without worsening renal function in patients in both groups: −4.00% vs. 1.46% (p = 0.020) for the diuretic group and −6.14% vs. 1.28% (p < 0.001) for the nondiuretic group. Furthermore, canagliflozin significantly reduced serum uric acid without causing major electrolyte abnormalities in patients in both subgroups. The long-term beneficial effect of SGLT2i on intravascular congestion could be independent of conventional diuretic therapy without worsening renal function in patients with T2D and HF (HFpEF predominantly). In addition, the beneficial effects of canagliflozin are accompanied by improved hyperuricemia without causing major electrolyte abnormalities.
Background
Gout or rapid reduction in serum uric acid level may increase the incidence of heart failure (HF). To compare the risk of HF between febuxostat and allopurinol in gout patients with coexisting cardiovascular (CV) diseases, the varying severity would be likely to confound the risk estimation. Gout and HF are both sex-related diseases, and the risk difference from the urate-lowering agents between women and men remains unknown.
Aims
To evaluate the HF hospitalisations risk of febuxostat and allopurinol in gout patients in real-world settings.
Methods
A population-based cohort enrolled patients with allopurinol or febuxostat initiation from 2011 to 2018. Participants were grouped into, without (low CV risk group) or with (high CV risk group) a history of recent major CV admission. The primary outcome was HF hospitalization. The secondary outcomes were composite CV events, all-cause mortality, and the cause of CV mortality. We used the ‘as-treated' analysis and Cox proportional hazards model after propensity score (PS) matching. Patients were further stratified into men and women to evaluate the gender differences.
Results
Febuxostat users had a significantly higher risk of HF hospitalization than allopurinol users in gout patients either with low CV risk [hazard ratio (HR) 1.39; 95% confidence interval (CI) 1.25–1.55] or high CV risk [HR 1.36; 95% CI 1.22–1.52]. Particularly, women with gout had a higher risk of HF hospitalization than men.
Conclusion
The HF hospitalization risk was highest in gout women with high CV risk and febuxostat use. Monitoring of HF is warranted in these patients.
Hyperoxia has been described to induce bradycardia by direct stimulation of the parasympathetic nervous system. Also, hyperoxia has been found to increase blood pressure by an elevation of vascular resistance. However, the latter effect itself would induce bradycardia by baroreceptor stimulation. This single-arm monocentric retrospective study aims to evaluate the correlation between these effects by investigating the relation between oxygen (O2) administration and heart rate over time. Data were collected from 23 patients without cardiovascular problems undergoing hyperbaric oxygen therapy (2.4 bar) retrospectively. During single oxygen bouts, transcutaneously measured partial pressure of O2 was increased. During this surge of oxygen pressure, the arterial blood pressure was increased while the heart rate was decreased. Respiration rate was maintained independently from breathing 100% O2 or air. During single oxygen bouts, the half-life of transcutaneously measured partial pressure of O2 was 5.4 ± 2.1 mmHg/s, and the half-life of heart rate was 0.45 ± 0.19 beats/min. It has been shown that hyperbaric oxygen therapy increases the transcutaneously measured partial pressure of O2. This increase was rather fast, followed by a rather slow decrease in HR. This finding does not support direct vagal activation. Heart rate is not decreased due to a direct vagal activation during hyperbaric oxygen therapy. Our single-arm, retrospective study has additionally confirmed that oxidative stress injures the endothelium, and the reduced endothelial-derived vasodilators cause vasoconstriction. As a consequence, blood pressure increases, and heart rate is then further decreased via the baroreceptor reflex.
Background
The benefits of xanthine oxidase inhibitors to chronic heart failure (CHF) patients is controversial. We investigated the beneficial effects of a novel xanthine oxidoreductase inhibitor, topiroxostat, in patients with CHF and hyperuricemia (HU), in comparison to allopurinol.
Methods and results
The prospective, randomized open-label, blinded-end-point study was performed in 141 patients with CHF and HU at 4 centers. Patients were randomly assigned to either topiroxostat or allopurinol group to achieve target uric acid level ≤6.0 mg/dL. According to the protocol, 140 patients were followed up for 24 weeks. Percent change in ln (N-terminal-proB-type natriuretic peptide) at week 24 (primary endpoint) was comparable between topiroxostat and allopurinol groups (1.6±8.2 versus -0.4±8.0%; P = 0.17). In the limited number of patients with heart failure with reduced ejection fraction (HFrEF) (left ventricle ejection fraction <45%), ratio of peak early diastolic flow velocity at mitral valve leaflet to early diastolic mitral annular motion velocity (E/e’) decreased in topiroxostat group, but not in allopurinol group. Urinary 8-hydroxy-2’-deoxyguanosine and L-type fatty acid-binding protein levels increased and osmolality decreased significantly in allopurinol group, while these changes were less or absent in topiroxostat group. In allopurinol group HFrEF patients, additional to the increases in these urinary marker levels, urinary creatinine levels decreased, with no change in clearance, but not in topiroxostat group.
Conclusions
Compared with allopurinol, topiroxostat did not show great benefits in patients with CHF and HU. However, topiroxostat might have potential advantages of reducing left ventricular end-diastolic pressure, not worsening oxidative stress in proximal renal tubule, and renoprotection over allopurinol in HFrEF patients.
Arterial endothelial dysfunction has been extensively studied in heart failure (HF). However little is known about the adjustments shown by the venous system in this condition. Considering that inferior vena cava (VC) tone could influence cardiac performance and HF prognosis, the aim of the present study was to assess the VC and thoracic aorta (TA) endothelial function of HF-post-myocardial infarction (MI) rats, comparing both endothelial responses and signaling pathways developed. Vascular reactivity of TA and VC from HF post-MI and sham operated (SO) rats was assessed with a wire myograph, four weeks after coronary artery occlusion surgery. Nitric oxide (NO), H2O2 production and oxidative stress were evaluated in situ with fluorescent probes, whilst protein expression and dimer/monomer ratio was assessed by western blot. VC from HF rats presented endothelial dysfunction, while TA exhibited higher acetylcholine (ACh)-induced vasodilation when compared to vessels from SO rats. TA exhibited increased ACh-induced NO production due to a higher coupling of endothelial and neuronal NO synthases isoforms (eNOS, nNOS), and enhanced expression of antioxidant enzymes. These adjustments, however, were absent in VC of HF post-MI rats, which exhibited uncoupled nNOS, oxidative stress and higher H2O2 bioavailability. Altogether, this study suggests a differential regulation of endothelial function between VC and TA of HF post-MI rats, most likely due to nNOS uncoupling and compromised antioxidant defense.
In this study, we aimed to investigate whether degree of pneumonia and COVID-19 prognosis are associated with serum endocan levels at the early stage, when vascular damage has started. Patients between the ages of 18–85 years who were hospitalized and followed up with a diagnosis of COVID-19 were included in the study. A total of 80 patients were divided into 2 groups as mild/moderate pneumonia and severe pneumonia. Serum endocan levels were measured on the 8th day from the onset of symptoms in all patients. Of the 80 patients included in the study, 56.3% were female and 43.8% were male. There was no significant relationship between serum endocan levels and degree of pneumonia ( P = .220) and prognosis of the disease ( P = .761). The correlation analysis indicated a weak positive correlation between serum endocan levels and lactate level in venous blood gas (r = .270; P = .037). During the 28-day follow-up, the mortality rate was 3.75%. It was determined that the serum endocan levels was not associated with the degree of pneumonia and was not an early prognostic marker for COVID-19.
Background
Type 2 diabetes is a risk factor for atherosclerosis. Oxidative stress, which is a causative factor in insulin resistance, leads to atherosclerosis in patients with diabetes. Xanthine oxidoreductase (XOR) is an enzyme that catalyzes the oxidation of hypoxanthine to xanthine and xanthine to uric acid and is related to oxidative stress. We aimed to examine the influence of plasma XOR activity on arterial stiffness in patients with type 2 diabetes.
Methods
In total, 458 patients with type 2 diabetes not receiving antihyperuricemic agents were enrolled and their clinical parameters including plasma XOR activity and the cardio-ankle vascular index (CAVI) were measured. Patients were divided into the liver dysfunction and absence of liver dysfunction groups. Multiple regression analysis was performed.
Results
The median plasma XOR activity level was 64.3 pmol/h/mL (33.3–147.3 pmol/h/mL). Plasma XOR activity was correlated significantly and positively with aspartate transaminase and alanine transaminase (ρ > 0.5). The level of plasma XOR activity in the liver dysfunction group was eight-fold higher than that in the absence of liver dysfunction group. A significant positive correlation was observed between plasma XOR activity and the CAVI only in the liver dysfunction group (ρ = 0.3968, P < 0.0043). Multiple regression models demonstrated that plasma XOR activity was an independent predictor of the CAVI in the liver dysfunction group (P = 0.0055).
Conclusions
Our results suggest that plasma XOR activity is associated with arterial stiffness and may have a role in atherosclerosis development in patients with type 2 diabetes and liver dysfunction.
Background
The role of serum uric acid (SUA) as an independent risk factor for coronary artery disease remains unclear. The aim of this study was to investigate whether the SUA levels could affect the incidence of major adverse cardiac events (MACE) after percutaneous coronary intervention (PCI).
Methods and results
We retrospectively examined the clinical records of 1,949 patients who underwent successful PCI. First, they were divided into two groups based on an SUA level of 7.0mg/dl. Among the two groups, the incidence of MACE was measured for a maximum of 5 years after PCI. Next, we divided them into 6 groups at SUA intervals of 1.0mg/dl and estimated the hazard ratios of each group. The Kaplan-Meier curve demonstrated that patients with SUA levels of >7.0mg/dl had a higher incidence of MACE than those with 7.0mg/dl or less. However, according to the multivariate analysis, the SUA level was not significantly correlated with the incidence of MACE because other factors could strongly affect it. Meanwhile, the group with SUA levels between 4.1-5.0mg/dl had a lower hazard ratio compared to groups with SUA levels of more than 5.1mg/dl. However, the hazard ratio of the group with SUA levels of 4.0mg or less was not lower than that of the group with SUA levels of 4.1-5.0mg/dl. Even after adjustment for several parameters, nearly the same results before adjustment were obtained for the hazard ratios of each group.
Conclusion
The present study demonstrated that the SUA level was one of the most valuable predictors of cardiovascular events after PCI, with elevated SUA levels adversely affecting secondary prevention.
Significance:
The vasculature responds to the respiratory needs of tissue by modulating luminal diameter through smooth muscle constriction or relaxation. Coronary perfusion, diastolic function, and coronary flow reserve are drastically reduced with aging. This loss of blood flow contributes to and exacerbates pathological processes such as angina pectoris, atherosclerosis, and coronary artery and microvascular disease. Recent Advances: Increased attention has recently been given to defining mechanisms behind aging-mediated loss of vascular function and development of therapeutic strategies to restore youthful vascular responsiveness. The ultimate goal aims to provide new avenues for symptom management, reversal of tissue damage, and preventing or delaying of aging-induced vascular damage and dysfunction in the first place.
Critical issues:
Our major objective is to describe how aging-associated mitochondrial dysfunction contributes to endothelial and smooth muscle dysfunction via dysregulated ROS production, the clinical impact of this phenomenon, and to discuss emerging therapeutic strategies. Pathological changes in regulation of mitochondrial oxidative and nitrosative balance (Section 1) and mitochondrial dynamics of fission/fusion (Section 2) have widespread effects on the mechanisms underlying the ability of the vasculature to relax, leading to hyperconstriction with aging. We will focus on flow-mediated dilation, endothelial hyperpolarizing factors (Sections 3-4), and adrenergic receptors (Section 5) as outlined in Figure 1. The clinical implications of these changes on major adverse cardiac events and mortality is described (Section 6).
Future directions:
We discuss antioxidative therapeutic strategies currently in development to restore mitochondrial redox homeostasis and subsequently vascular function and evaluate their potential clinical impact (Section 7).
Despite advances in medical and device therapy, patients with heart failure remain at high risk for morbidity and mortality. Experimental and clinical studies have shown an association between heart failure and a hypercoagulable state, and that patients with heart failure experience an increased incidence of stroke and other thromboembolic events, regardless of whether they are in atrial fibrillation. Although oral anticoagulation is recommended when atrial fibrillation is present, the benefits of this therapy in patients with heart failure in sinus rhythm are uncertain. Older randomized controlled trials comparing warfarin with antiplatelet therapy were, for the most part, underpowered and failed to show convincing benefits of warfarin therapy in this population. Several recent studies that assessed the effects of low-dose direct-acting oral anticoagulant therapy in patients with coronary artery disease in sinus rhythm either included or specifically targeted patients with heart failure. Post hoc analysis of their results showed that this treatment strategy was associated with improved outcomes in patients with acute coronary syndrome or stable coronary artery disease and also a significant reduction in thromboembolic events, including ischemic stroke. This review presents the rationale for anticoagulant therapy in patients with heart failure in sinus rhythm, discusses gaps in our knowledge base, offers suggestions for when anticoagulation might be considered, and identifies potential directions for future research.
An enzyme which catalyzes the dismutation of superoxide radicals (O2·⁻ + O2·⁻ + 2H⁺ → O2 + H2O2) has been purified by a simple procedure from bovine erythrocytes. This enzyme, called superoxide dismutase, contains 2 eq of copper per mole of enzyme. The copper may be reversibly removed, and it is required for activity. Superoxide dismutase has been shown to be identical with the previously described copper-containing erythrocuprein (human) and hemocuprein (bovine).
Stable solutions of the superoxide radical were generated by the electrolytic reduction of O2 in an aprotic solvent, dimethylformamide. Slow infusion of such solutions into buffered aqueous media permitted the demonstration that O2·⁻ can reduce ferricytochrome c and tetranitromethane, and that superoxide dismutase, by competing for the superoxide radicals, can markedly inhibit these reactions.
Superoxide dismutase was used to show that the oxidation of epinephrine to adrenochrome by milk xanthine oxidase is mediated by the superoxide radical.
An assay of several tissues indicates that superoxide dismutase is widely distributed within mammalian organisms.
Although cachexia often accompanies advanced heart failure, little is known about the causes of the cachectic state. To assess the potential role of tumor necrosis factor in the pathogenesis of cardiac cachexia, we measured serum levels of the factor in 33 patients with chronic heart failure, 33 age-matched healthy controls, and 9 patients with chronic renal failure.
Mean (+/- SEM) serum levels of tumor necrosis factor were higher in the patients with heart failure (115 +/- 25 U per milliliter) than in the healthy controls (9 +/- 3 U per milliliter; P less than 0.001). Nineteen of the patients with chronic heart failure had serum levels of tumor necrosis factor greater than or equal to 39 U per milliliter (greater than 2 SD above the mean value for the control group), whereas the remaining 14 patients had serum levels of tumor necrosis factor below this level. The patients with high levels of tumor necrosis factor were more cachectic than those with low levels (82 +/- 3 vs. 95 +/- 6 percent of ideal body weight, respectively; P less than 0.05) and had more advanced heart failure, as evidenced by their higher values for plasma renin activity (2.92 +/- 0.53 vs. 1.06 +/- 0.53 ng per liter per second [10.5 +/- 1.9 vs. 3.8 +/- 1.9 ng per milliliter per hour]; P less than 0.01) and lower serum sodium concentration (135 +/- 1 vs. 138 +/- 1 mmol per liter; P less than 0.05). The group with high levels of tumor necrosis factor also had lower hemoglobin levels (7.82 +/- 0.2 vs. 8.69 +/- 0.4 mmol per liter [12.6 +/- 0.4 vs. 14.0 +/- 0.6 g per deciliter]) and higher values for blood urea nitrogen (19.5 +/- 2.2 vs. 12.5 +/- 1.8 mmol per liter) than the group with low levels of tumor necrosis factor (P less than 0.05 for both). The high levels of tumor necrosis factor were not due solely to decreased renal clearance, however, since the levels in the patients with heart failure were considerably higher than those in the nine patients with chronic renal failure (115 +/- 25 vs. 45 +/- 25 U per milliliter; P less than 0.05).
These findings indicate that circulating levels of tumor necrosis factor are increased in cachectic patients with chronic heart failure and that this elevation is associated with the marked activation of the renin-angiotensin system seen in patients with end-stage cardiac disease.
Rat pulmonary artery endothelial cells incubated with human serum that has been complement-activated by addition of cobra venom factor reveal a pronounced conversion of xanthine dehydrogenase to xanthine oxidase. This process requires the availability of the fifth component of complement (C5) but not the presence of other components (C2 and C6-C9). The phenomenon can be reproduced by addition to endothelial cells of purified human recombinant C5a but not C5a desArg or C3a. The enzyme conversion process is relatively rapid (occurring within 5-10 min), requires the presence of intact endothelial cells, and does not require protein synthesis. Similar effects on endothelial cells have been obtained with human recombinant tumor necrosis factor alpha and the chemotactic peptide N-formyl-Met-Leu-Phe. In contrast, bradykinin, recombinant human interleukin 1 beta, and phorbol ester lack this biological activity. These findings suggest novel effects of inflammatory mediators on endothelial cells.
Xanthine oxidase and xanthine dehydrogenase are enzymes involved in the metabolism of purines and pyrimidines in various organisms. Their relationship to one another has been the subject of considerable debate, primarily because of their proposed roles in ischemia/reperfusion damage in tissues. Differences in the kinetics and oxidation-reduction behavior of the two forms are accounted for by the presence in the dehydrogenase of a binding site for NAD+, as well as a substantially lower reduction potential for the flavin FADH./FADH2 couple of the dehydrogenase relative to the oxidase. This review presents recent advances of our understanding of the biochemistry and molecular biology of these systems, including a model for the overall morphology of xanthine oxidizing enzymes. The evidence that the two enzymes represent alternate forms of the same gene product, in some cases reversibly interconvertible between one another, is discussed.
Reactive oxygen species play a central role in vascular inflammation and atherogenesis, with enhanced superoxide (O2.-) production contributing significantly to impairment of nitric oxide (.NO)-dependent relaxation of vessels from cholesterol-fed rabbits. We investigated potential sources of O2.- production, which contribute to this loss of endothelium-dependent vascular responses. The vasorelaxation elicited by acetylcholine (ACh) in phenylephrine-contracted, aortic ring segments was impaired by cholesterol feeding. Pretreatment of aortic vessels with either heparin, which competes with xanthine oxidase (XO) for binding to sulfated glycosaminoglycans, or the XO inhibitor allopurinol resulted in a partial restoration (36-40% at 1 muM ACh) of ACh-dependent relaxation. Furthermore, O2.(-)-dependent lucigenin chemiluminescence, measured in intact ring segments from hypercholesterolemic rabbits, was decreased by addition of heparin, allopurinol or a chimeric, heparin-binding superoxide dismutase. XO activity was elevated more than two-fold in plasma of hypercholesterolemic rabbits. Incubation of vascular rings from rabbits on a normal diet with purified XO (10 milliunits/ml) also impaired .NO-dependent relaxation but only in the presence of purine substrate. As with vessels from hypercholesterolemic rabbits, this effect was prevented by heparin and allopurinol treatment. We hypothesize that increases in plasma cholesterol induce the release of XO into the circulation, where it binds to endothelial cell glycosaminoglycans. Only in hypercholesterolemic vessels is sufficient substrate available to sustain the production of O2.- and impair NO-dependent vasorelaxation. Chronically, the continued production of peroxynitrite, (ONOO-) which the simultaneous generation of NO and O2.- implies, may irreversibly impair vessel function.
Background:
Elevated serum uric acid concentrations have been observed in clinical conditions associated with hypoxia. Since chronic heart failure is a state of impaired oxidative metabolism, we sought to determine whether serum uric acid concentrations correlate with measures of functional capacity and disease severity.
Methods:
Fifty nine patients with a diagnosis of chronic heart failure due to coronary heart disease (n = 34) or idiopathic dilated cardiomyopathy (n = 25) and 20 healthy controls underwent assessment of functional capacity. Maximal oxygen uptake (MVO2) and regression slope relating to minute ventilation to carbon dioxide output (VE-VCO2) were measured during a maximal treadmill exercise test. Metabolic assessment consisted of measuring serum uric acid and fasting lipids, and insulin sensitivity, obtained by minimal modelling analysis of glucose and insulin responses during an intravenous glucose tolerance test. Clustering of indices of functional disease capacity and metabolic factors was explored using factor analysis and multivariate regression analysis.
Results:
Compared to 20 healthy controls, patients with chronic heart failure had a 52% lower MVO2 (P < 0.001), 56.8% higher serum uric acid concentrations (P < 0.001) as well as a 60.5% lower insulin sensitivity (P < 0.001). Salient univariate correlations in the chronic heart failure group included serum uric acid concentrations with exercise time during the exercise test (r = -0.53), MVO2 (r = -0.50) (both P < 0.001), VE-VCO2 slope (r = 0.45), and NYHA functional class (r = 0.36) (both P < 0.01). In factor analysis of the chronic heart failure group, serum uric acid formed part of a principal cluster of metabolic variables which included MVO2 and VE-VCO2 slope. In multivariate regression analysis, serum uric acid concentrations emerged as a significant predictor of MVO2, exercise time (both P < 0.001,) VE-VCO2 slope and NYHA functional class (both P < 0.02), independent of diuretic dose, age, body mass index, serum creatinine, alcohol intake, plasma insulin levels, and insulin sensitivity index.
Conclusions:
There is an inverse relationship between serum uric acid concentrations and measures of functional capacity in patients with cardiac failure. The strong correlation between serum uric acid and MVO2 suggests that in chronic heart failure, serum uric acid concentrations reflect an impairment of oxidative metabolism.
Concentrations of up to 1.5 milliunits/ml xanthine oxidase (XO) (1.1 micrograms/ml) are found circulating in plasma during diverse inflammatory events. The saturable, high affinity binding of extracellular XO to vascular endothelium and the effects of cell binding on both XO catalytic activity and differentiated vascular cell function are reported herein. Xanthine oxidase purified from bovine cream bound specifically and with high affinity (Kd = 6 nM) at 4 degreesC to bovine aortic endothelial cells, increasing cell XO specific activity up to 10-fold. Xanthine oxidase-cell binding was not inhibited by serum or albumin and was partially inhibited by the addition of heparin. Pretreatment of endothelial cells with chondroitinase, but not heparinase or heparitinase, diminished endothelial binding by approximately 50%, suggesting association with chondroitin sulfate proteoglycans. Analysis of rates of superoxide production by soluble and cell-bound XO revealed that endothelial binding did not alter the percentage of univalent reduction of oxygen to superoxide. Comparison of the extent of CuZn-SOD inhibition of native and succinoylated cytochrome c reduction by cell-bound XO indicated that XO-dependent superoxide production was occurring in a cell compartment inaccessible to CuZn-SOD. This was further supported by the observation of a shift of exogenously added XO from extracellular binding sites to intracellular compartments, as indicated by both protease-reversible cell binding and immunocytochemical localization studies. Endothelium-bound XO also inhibited nitric oxide-dependent cGMP production by smooth muscle cell co-cultures in an SOD-resistant manner. This data supports the concept that circulating XO can bind to vascular cells, impairing cell function via oxidative mechanisms, and explains how vascular XO activity diminishes vasodilatory responses to acetylcholine in hypercholesterolemic rabbits and atherosclerotic humans. The ubiquity of cell-XO binding and endocytosis as a fundamental mechanism of oxidative tissue injury is also affirmed by the significant extent of XO binding to human vascular endothelial cells, rat lung type 2 alveolar epthelial cells, and fibroblasts.
Observational and experimental studies suggest that the amount of vitamin E ingested in food and in supplements is associated with a lower risk of coronary heart disease and atherosclerosis.
We enrolled a total of 2545 women and 6996 men 55 years of age or older who were at high risk for cardiovascular events because they had cardiovascular disease or diabetes in addition to one other risk factor. These patients were randomly assigned according to a two-by-two factorial design to receive either 400 IU of vitamin E daily from natural sources or matching placebo and either an angiotensin-converting-enzyme inhibitor (ramipril) or matching placebo for a mean of 4.5 years (the results of the comparison of ramipril and placebo are reported in a companion article). The primary outcome was a composite of myocardial infarction, stroke, and death from cardiovascular causes. The secondary outcomes included unstable angina, congestive heart failure, revascularization or amputation, death from any cause, complications of diabetes, and cancer.
A total of 772 of the 4761 patients assigned to vitamin E (16.2 percent) and 739 of the 4780 assigned to placebo (15.5 percent) had a primary outcome event (relative risk, 1.05; 95 percent confidence interval, 0.95 to 1.16; P=0.33). There were no significant differences in the numbers of deaths from cardiovascular causes (342 of those assigned to vitamin E vs. 328 of those assigned to placebo; relative risk, 1.05; 95 percent confidence interval, 0.90 to 1.22), myocardial infarction (532 vs. 524; relative risk, 1.02; 95 percent confidence interval, 0.90 to 1.15), or stroke (209 vs. 180; relative risk, 1.17; 95 percent confidence interval, 0.95 to 1.42). There were also no significant differences in the incidence of secondary cardiovascular outcomes or in death from any cause. There were no significant adverse effects of vitamin E.
In patients at high risk for cardiovascular events, treatment with vitamin E for a mean of 4.5 years had no apparent effect on cardiovascular outcomes.
Increased inactivation of nitric oxide by oxygen free radicals contributes to endothelial dysfunction in patients with coronary artery disease (CAD). We therefore determined the activity of extracellular superoxide dismutase (EC-SOD), the major antioxidant enzyme system of the vessel wall, and its relation to flow-dependent, endothelium-mediated dilation (FDD) in patients with CAD.
SOD isoenzyme activity was determined in coronary arteries from 10 patients with CAD and 10 control subjects. In addition, endothelium-bound EC-SOD activity (eEC-SOD), released by heparin bolus injection, and FDD of the radial artery were measured in 35 patients with CAD and 15 control subjects. FDD, determined by high-resolution ultrasound, was assessed at baseline, after intra-arterial infusion of vitamin C, N-monomethyl-L-arginine, and combination of both. EC-SOD activity in coronary arteries (control subjects: 126+/-14; CAD: 63+/-11 U/mg protein; P<0.01) and eEC-SOD activity in vivo (control subjects: 14.5+/-1.1; CAD: 3.8+/-1.1 U. mL(-1). min(-1); P<0.01) were reduced in patients with CAD. Activity of eEC-SOD was positively correlated with FDD (r=0.47; P<0. 01) and negatively with the effect of the antioxidant vitamin C on FDD (r=-0.59; P<0.01). In young individuals with hypercholesterolemia, however, eEC-SOD activity was increased (21. 0+/-1.2 U. mL(-1). min(-1); n=10; P<0.05).
In patients with CAD, vascular EC-SOD activity is substantially reduced. The close relation between endothelium-bound EC-SOD activity and FDD suggests that reduced EC-SOD activity contributes to endothelial dysfunction in patients with CAD. In young hypercholesterolemic individuals, however, endothelium-bound EC-SOD activity is increased and may, in part, counteract impairment of endothelial function as the result of increased formation of oxygen free radicals.
The bioactivity of endothelium-derived nitric oxide (NO) reflects its rates of production and of inactivation by superoxide (O(2)(*-)), a reactive species dismutated by extracellular superoxide dismutase (ecSOD). We have now examined the complementary hypothesis, namely that NO modulates ecSOD expression. The NO donor DETA-NO increased ecSOD expression in a time- and dose-dependent manner in human aortic smooth muscle cells. This effect was prevented by the guanylate cyclase inhibitor ODQ and by the protein kinase G (PKG) inhibitor Rp-8-CPT-cGMP. Expression of ecSOD was also increased by 8-bromo-cGMP, but not by 8-bromo-cAMP. Interestingly, the effect of NO on ecSOD expression was prevented by inhibition of the MAP kinase p38 but not of the MAP kinase kinase p42/44, suggesting that NO modulates ecSOD expression via cGMP/PKG and p38MAP kinase-dependent pathways, but not through p42/44MAP kinase. In aortas from mice lacking the endothelial nitric oxide synthase (eNOS), ecSOD was reduced more than twofold compared to controls. Treadmill exercise training increased eNOS and ecSOD expression in wild-type mice but had no effect on ecSOD expression in mice lacking eNOS, suggesting that this effect of exercise is meditated by endothelium-derived NO. Upregulation of ecSOD expression by NO may represent an important feed-forward mechanism whereby endothelial NO stimulates ecSOD expression in adjacent smooth muscle cells, thus preventing O(2)(*-)-mediated degradation of NO as it traverses between the two cell types.
Mammalian xanthine oxidoreductases, which catalyze the last two steps in the formation of urate, are synthesized as the dehydrogenase form xanthine dehydrogenase (XDH) but can be readily converted to the oxidase form xanthine oxidase (XO) by oxidation of sulfhydryl residues or by proteolysis. Here, we present the crystal structure of the dimeric (M(r), 290,000) bovine milk XDH at 2.1-A resolution and XO at 2.5-A resolution and describe the major changes that occur on the proteolytic transformation of XDH to the XO form. Each molecule is composed of an N-terminal 20-kDa domain containing two iron sulfur centers, a central 40-kDa flavin adenine dinucleotide domain, and a C-terminal 85-kDa molybdopterin-binding domain with the four redox centers aligned in an almost linear fashion. Cleavage of surface-exposed loops of XDH causes major structural rearrangement of another loop close to the flavin ring (Gln 423Lys 433). This movement partially blocks access of the NAD substrate to the flavin adenine dinucleotide cofactor and changes the electrostatic environment of the active site, reflecting the switch of substrate specificity observed for the two forms of this enzyme.
Background. Abnormalities in endothelium-dependent relaxation to acetylcholine have been reported in congestive heart failure (CHF). The purpose of this study was to determine whether there are abnormalities in flow-mediated large vessel relaxation in patients with chronic CHF. Methods and Results. The dilator response of the radial artery was measured by a new high precision A-mode ultrasound device in response to release of 10 minutes of forearm arterial occlusion (reactive hyperemic blood flow response, RHBF). Radial arterial blood velocity was measured simultaneously, and blood flow was calculated. In nine patients with chronic CHF, there was a small but insignificant reduction of peak RHFB (p=0.09) when compared with nine age-matched control subjects. The increase in arterial diameter that followed the peak blood flow was significantly reduced in CHF (normal: 14.98±2.47%; CHF: 7.58±0.89%; p<0.01). In addition, the time to peak arterial relaxation was delayed (normal: 57.8±9.4 seconds; CHF: 98.9±15 seconds; p<0.02). When the peak percent increase in diameter was divided by the magnitude of the peak blood flow response, differences in the CHF and normal groups persisted. Conclusions. These data indicate that flow-mediated large artery relaxation is abnormal in CHF. It is suggested that both structural and endothelium-dependent abnormalities may contribute to this abnormal response.
Background There is conflicting evidence on the benefits of foods rich in vitamin E (alpha-tocopherol), n-3 polyunsaturated fatty acids (PUFA), and their pharmacological substitutes. We investigated the effects of these substances as supplements in patients who had myocardial infarction. Methods From October, 1993, to September, 1995, 11324 patients surviving recent (less than or equal to 3 months) myocardial infarction were randomly assigned supplements of n-3 PUFA (Ig daily, n=2836), vitamin E (300 mg daily, n=2830), both (n=2830), or none (control, n=2828) for 3.5 years. The primary combined efficacy endpoint was death, non-fatal myocardial infarction, and stroke. Intention-to-treat analyses were done according to a factorial design (two-way) and by treatment group (four-way). Findings Treatment with n-3 PUFA, but not vitamin E, significantly lowered the risk of the primary endpoint (relative risk decrease 10% [95% CI 1-18] by two-way analysis, 15% [2-26] by four-way analysis). Benefit was attributable to a decrease in the risk of death (14% [3-24] two-way, 20% [6-33] four-way) and cardiovascular death (17% [3-29] two-way, 30% [13-44] four-way). The effect of the combined treatment was similar to that for n-3 PUFA for the primary endpoint (14% [1-26]) and for fatal events (20% [5-33]). Interpretation Dietary supplementation with n-3 PUFA led to a clinically important and satistically significant benefit. Vitamin E had no benefit. Its effects on fatal cardiovascular events require further exploration.
Superoxide dismutase (SOD) activity was measured by seven assay methods. The nitrite method was found to be the best for our SOD assay kit. This method was then modified to give better sensitivity and minimize interference by coexisting protein, a factor which has been previously ignored. Hydroxylamine or its O-sulfonic acid, xanthine oxidase, hypoxanthine, EDTA, and the sample were incubated with or without KCN at pH 8.2, 37°C, for 30 min. Diazo dye-forming reagent was added and the absorption was measured at 550 nm. Human plasma and erythrocyte lysate from healthy adults and Down's syndrome patients were assayed by this SOD kit and by the cytochrome c method. Our kit gave 8.5 times higher sensitivity than the cytochrome c method. This high sensitivity allowed the use of a simple spectrophotometer and, moreover, only one dilution was needed to determine the SOD unit with the help of our formulas. Good recovery, reproducibility, and stability of reagents were demonstrated.
Nitric oxide (NO) and superoxide are both constitutive products of the endothelium. Because NO is readily inactivated by superoxide, the bioactivity of endothelium-derived NO (EDNO) is dependent on local activity of superoxide dismutase (SOD). We examined the effects of chronic inhibition of copper-zinc SOD (CuZnSOD) using a rat model of dietary copper restriction. Male weanling Sprague-Dawley rats were fed a Cu-deficient diet and received either no Cu replacement (Cu-deficient) or Cu in the drinking water (Cu-sufficient). Compared with Cu-sufficient animals, Cu-deficiency was associated with a 68% reduction in CuZnSOD activity and a 58% increase in vascular superoxide as estimated by lucigenin chemiluminescence (both P<.05). Compared with Cu-sufficient animals, arterial relaxation in the thoracic aorta from Cu-deficient animals was 10-fold less sensitive to acetylcholine, a receptor-dependent EDNO agonist, but only 1.5-fold less sensitive to A23187, a receptor-independent EDNO agonist, and only 1.25-fold less sensitive to authentic NO (all P<.05). In contrast, acute inhibition of CuZnSOD with 10 mM diethyldithiocarbamate produced a more uniform reduction in sensitivity to acetylcholine (8-fold), A23187 (10-fold), and NO (4-fold; all P<.001). Cu-deficient animals demonstrated a 2.5-fold increase in plasma-esterified F2-isoprostanes, a stable marker of lipid peroxidation, that correlated inversely with arterial relaxation to acetylcholine (R=-.83; P<.0009) but not A23187 or authentic NO. From these findings, we conclude that chronic inhibition of CuZnSOD inhibits EDNO-mediated arterial relaxation through two mechanisms, one being direct inactivation of NO and the other being lipid peroxidation that preferentially interrupts receptor-mediated stimulation of EDNO.
Extracellular superoxide dismutase type C (EC-SOD C) is a secretory SOD isoenzyme that, in vivo, is bound to heparan sulfate proteoglycans in the glycocalyx of various cell types (e.g., endothelial cells) and in the connective tissue matrix. The aim of this study was to investigate the efficacy of vascular bound EC-SOD C in protecting arterial relaxation mediated by endothelium-derived relaxing factor (EDRF) against the inhibitory effects of superoxide radicals. For comparison, the effect of CuZn SOD was also studied. This SOD isoenzyme lacks affinity toward heparan sulfate and does not bind to cell surfaces. Rings from rabbit aorta were mounted in an organ bath and acetylcholine-induced endothelium-dependent relaxation was then studied in preparations precontracted with phenylephrine. Pyrogallol (10(-4) M), used to generate superoxide radicals, reduced the maximal relaxant effect of acetylcholine from about 65% to 25%. When present in the buffer throughout the experiment, CuZn SOD and EC-SOD C caused a concentration-dependent prevention of the pyrogallol effect on EDRF-mediated relaxation, with a half-maximal effect at about 100 units/ml (KO2 assay). In a second set of experiments, the arterial rings were preincubated with 8,000 units/ml CuZn SOD (50 micrograms/ml) or EC-SOD C (69 micrograms/ml) during 30 minutes, followed by washing, before the effect of pyrogallol on EDRF-mediated relaxation was studied in SOD-free buffer.(ABSTRACT TRUNCATED AT 250 WORDS)
There is evidence that the endothelium plays an important role in the control of human vascular tone by releasing endothelium-derived nitric oxide. The hypothesis that an impairment of this mechanism is involved in the increased peripheral vasoconstriction of patients with chronic congestive heart failure (CHF) was tested. Acetylcholine and N-monomethyl-L-arginine (L-NMMA), a specific inhibitor of nitric oxide synthesis from L-arginine, were infused in the brachial artery of healthy volunteer subjects (controls) and patients with severe CHF. The radial artery diameter was determined by a high-precision A-mode ultrasound device, using a 10 MHz probe. Forearm blood flow was calculated from vessel diameter and blood flow velocity measured simultaneously by Doppler. The blood flow response to acetylcholine was blunted in patients with CHF compared with that in control subjects. In contrast, the decrease in blood flow induced by L-NMMA was exaggerated in CHF, and the blood flow response to nitroglycerin was preserved. The changes in radial artery diameter induced by acetylcholine and L-NMMA were not significant in control subjects and CHF patients, but dilation of the radial artery by nitroglycerin was significantly reduced in CHF. The results demonstrate an impaired endothelium-dependent dilation of forearm resistance vessels in CHF, suggesting a reduced release of nitric oxide on stimulation. In contrast, the basal release of nitric oxide from endothelium of forearm resistance vessels is preserved or may even be enhanced, and may play an important compensatory role in chronic CHF by antagonizing neurohumoral vasoconstrictor forces in CHF.
Isolated bovine coronary arteries were treated with 10 mM diethyldithiocarbamate (DETCA) for 30 minutes to deplete the cytosolic ZnCu form of superoxide dismutase (SOD). This treatment completely inhibited the endothelium- and cGMP-dependent relaxation to acetylcholine (mediated via the endothelium-derived relaxing factor, which is thought to be nitric oxide) without significantly inhibiting endothelium-dependent relaxation to arachidonic acid (mediated by prostaglandins). DETCA treatment of endothelial cells cultured from the coronary arteries inhibited bradykinin-elicited release of endothelium-derived relaxing factor, which was detected by bioassay on an isolated rabbit aorta in the presence of extracellular SOD. DETCA also inhibited cGMP-associated relaxations to nitric oxide and to vasodilators thought to function via the generation of this mediator (nitroglycerin and nitroprusside), but cAMP-associated relaxations to isoproterenol and papaverine were not altered. The inhibitory effects of DETCA against the relaxation to nitroprusside and nitroglycerin were attenuated by severe hypoxia. DETCA treatment of isolated coronary arterial smooth muscle or cultured endothelial cells produced an increase of chemiluminescence elicited in the presence of lucigenin, a detector of superoxide anion generation. The addition of SOD markedly attenuated the effects of DETCA treatment on arterial relaxation and chemiluminescence. Therefore, control of cellular superoxide anion levels by endogenous SOD appears needed for the release of endothelium-derived relaxing factor and relaxation of vascular smooth muscle to nitrovasodilators mediated via cGMP in the bovine coronary artery, but SOD is not critical for other endothelium-dependent or cAMP-associated relaxant mechanisms.
Endothelium-derived relaxing factor (EDRF) is rapidly inactivated by radicals. Endothelial cells possess several antioxidant defense mechanisms. It is not clear which intrinsic antioxidant defense systems are important to preserve the release of biologically active EDRF. We impaired antioxidant defense in normal vascular tissue by inhibiting catalase activity with 3-amino-1,2,4-triazole (AT), superoxide dismutase with diethyldithiocarbamate (DETC), and by reducing glutathione content via inhibiting glutathione synthesis with L-buthionine-(S,R)-sulfoximine (BSO). Pretreatment of rabbit aorta in vitro with DETC markedly reduced endothelium-dependent relaxation in response to acetylcholine and calcium ionophore A23187 and, to a lesser extent, reduced endothelium-independent relaxation in response to nitroprusside. Pretreatment of cultured bovine aortic endothelial cells (BAEC) with DETC did not alter release of nitrogen oxides (measured by chemiluminescence), but, the effluent of pretreated cells showed marked depression in vasodilator activity (measured by bioassay). Pretreatment of rabbit aorta in vitro with AT did not alter endothelium-dependent and -independent relaxations. Pretreatment of BAEC with BSO did not alter the release of nitrogen oxides or the vasodilator activity. These results suggest that endothelial superoxide dismutase activity, but not catalase or glutathione, is necessary for the release of biologically active EDRF. An imbalance of the intrinsic superoxide dismutase and the production of superoxide anions may therefore predispose to impaired endothelium-dependent relaxations and alter vascular reactivity.
Endothelial cells produce a number of substances, collectively termed endothelium-derived relaxing factor (EDRF), that promote local relaxation of vascular smooth muscle. Although studies have demonstrated defects in endothelium-dependent vasodilation in animal models of hypertension, atherosclerosis, and heart failure, there are only limited data from human subjects because of the difficulty in obtaining fresh vascular segments.
To address the hypothesis that endothelium-dependent vasodilation is attenuated in patients with heart failure, we measured forearm blood flow responses to the intra-arterial administration of methacholine, a known stimulus of EDRF release through muscarinic receptors. In 14 normal subjects, a dosage range of methacholine increased forearm blood flow by 5.26 +/- 0.63, 10.50 +/- 0.63, and 13.22 +/- 0.86 ml/min/100 ml forearm volume (FAV); these responses were 1.98 +/- 0.46, 5.48 +/- 0.79, and 8.50 +/- 1.53 ml/min/100 ml FAV in 14 patients with heart failure. When pooled over all doses, the responses were strikingly less in the patients with heart failure (5.32 +/- 0.31 versus 9.52 +/- 0.60 ml/min/100 ml FAV; p = 0.0003). In a second study, the average difference in forearm blood flow responses between patients with heart failure and normal subjects with methacholine was significantly greater than the average difference between the groups with nitroprusside (4.04 +/- 1.10 versus 2.20 +/- 0.71 ml/min/100 ml FAV; p = 0.04). The decreased methacholine responses in the patients with heart failure were not related to age (r = 0.39; p = NS) or etiology because there was no difference in the responses between patients with ischemic heart disease and those with idiopathic cardiomyopathy.
These data suggest that endothelium-dependent vasodilation is attenuated in patients with heart failure. Although the mechanisms of the decreased endothelium-dependent responses in heart failure are not known, this impaired local vasodilation may contribute to abnormalities in vasoconstriction that are characteristic of heart failure.
Extracellular superoxide dismutase (EC-SOD) is the major SOD isoenzyme in extracellular fluids, but occurs also in tissues. The sites and characteristics of the synthesis of the enzyme are unknown. The occurrence of EC-SOD in cultures of a large panel of human cell lines was assayed by means of an e.l.i.s.a. Unlike the situation for the intracellular isoenzymes CuZn-SOD and Mn-SOD, expression of EC-SOD occurs in only a few cell types. None of the ten investigated suspension-growing cell lines produced EC-SOD. Among normal diploid anchorage-dependent cell lines, expression was found in all 25 investigated fibroblast cell lines, in the two glia-cell lines, but not in six endothelial-cell lines, two epithelial-cell lines or in two amnion-derived lines. Among neoplastic anchorage-dependent cell lines expression was found in 13 out of 29. EC-SOD was secreted into the culture medium by cell lines expressing the enzyme. The rate of EC-SOD synthesis varied by nearly 100-fold among the fibroblast lines and remained essentially constant in the individual lines during long-term culture. In the nine investigated cases, the secreted EC-SOD was of the high-heparin-affinity C type. It is suggested that tissue EC-SOD is secreted by a few well-dispersed cell types, such as fibroblasts and glia cells, to diffuse subsequently around and reversibly bind to heparan sulphate proteoglycan ligands in the glycocalyx of the surface of most tissue cell types and in the interstitial matrix.
Dilator reserve of the coronary microvasculature is diminished in patients with dilated cardiomyopathy. Although increased extravascular compressive forces, tachycardia, and increased myocardial mass can explain some impairment, recent evidence suggests the possibility of intrinsic microvascular disease. We tested the hypothesis that impairment of endothelium-dependent dilation of the microvasculature could be a contributing mechanism. We infused the endothelium-dependent dilator acetylcholine (Ach) (10(-8) to 10(-6) M) and the smooth muscle vasodilator adenosine (AD) (10(-6) to 10(-4) M) into the left anterior descending coronary artery in eight patients with dilated cardiomyopathy (mean ejection fraction, 28%) and seven controls (atypical chest pain). Small vessel resistance was assessed by measuring coronary blood flow (CBF) at constant arterial pressure with a Doppler velocity catheter (corrected for cross-sectional area by angiography). With Ach, control patients increased CBF 232 +/- 40% (mean +/- SEM), whereas CBF did not significantly change in cardiomyopathy patients (41 +/- 24%) (p less than 0.0001, control vs. cardiomyopathy). With AD, control patients increased CBF 422 +/- 56% and cardiomyopathy patients increased CBF 268 +/- 43% (p = 0.13). An index of the proportion of coronary flow reserve attributable to endothelium-dependent vasodilation was obtained by standardizing each patient's Ach dose response to his maximal AD flow response. In seven control patients receiving both Ach and AD, 56 +/- 9% of the maximal AD flow response was attained with the endothelium-dependent vasodilator Ach, whereas in seven cardiomyopathy patients receiving both Ach and AD, only 23 +/- 14% of the maximal AD response was attained (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
Extracellular superoxide dismutase (SOD) has previously been shown to be the major SOD isoenzyme in extracellular fluids. Upon chromatography on heparin-Sepharose it was separated into three fractions: A, without affinity; B, with intermediate affinity; and C, with relatively strong heparin affinity. Intravenous injection of heparin leads to a prompt increase in plasma extracellular-superoxide-dismutase (EC-SOD) activity. Heparin induces no release of EC-SOD from blood cells, nor does it activate EC-SOD in plasma, indicating that the source of the released enzyme is the endothelial-cell surfaces. No distinct saturation could be demonstrated in a dose-response curve up to 200 i.u. of heparin per kg body weight, showing that the releasing potency of heparin is lower for EC-SOD than for previously investigated heparin-released factors. Chromatography of human plasma on heparin-Sepharose shows nearly equal amounts of EC-SOD fractions A, B and C. Heparin induces specifically the release of fraction C. The findings point to the existence of an equilibrium of EC-SOD fraction C between the plasma phase and endothelial-cell surfaces. The major part of EC-SOD in the vasculature seems to be located on endothelial-cell surfaces.
Extracellular-superoxide dismutase is a tetrameric copper-containing glycoprotein that previously has been demonstrated to be the major superoxide dismutase of human extracellular fluids. The occurrence of this enzyme in various human tissues that were removed from two accidental death victims and in 19 different human cultured cell lines was determined. All investigated tissues were found to contain extracellular-superoxide dismutase. There was a larger variation between tissues in the concentration of this enzyme than in CuZn superoxide dismutase and Mn superoxide dismutase. No relation could be demonstrated between the content of extracellular-superoxide dismutase and the content of the other superoxide dismutase isoenzymes in the various tissues. In uterus there was more extracellular-superoxide dismutase than Mn superoxide dismutase, but in all other tissues the content of extracellular-superoxide dismutase was lower than the content of the other isoenzymes. The concentration of extracellular-superoxide dismutase was higher in all investigated human tissues than in human plasma. 19 human cultured cell lines were found to be devoid of or to contain very little extracellular-superoxide dismutase. Most tissues contained more extracellular-superoxide dismutase than did the investigated cell lines.
The levels of the secreted, interstitially located extracellular superoxide dismutase (EC-SOD), the cytosolic copper-and-zinc-containing SOD (CuZn-SOD), and the mitochondrial manganese-containing SOD (Mn-SOD) were measured in the walls of human coronary arteries, proximal thoracic aortas, and saphenous veins. The blood vessel walls, particularly the arteries, were found to contain exceptionally large amounts of EC-SOD, whereas the levels of CuZn-SOD and Mn-SOD were relatively low compared with other tissues. Analysis of EC-SOD by immunohistochemistry indicates an even distribution in the vessel wall, including large amounts of the arterial intima. Arterial smooth muscle cells were found to secrete large amounts of EC-SOD and likely are the principal source of the enzyme in the vascular wall. The EC-SOD concentration in the human arterial wall extracellular space is high enough to efficiently suppress the putative pathological effects of the superoxide radical, such as oxidation of LDL and reaction with nitric oxide to form the deleterious peroxynitrite. The levels of EC-SOD in the aortic wall are found to vary widely among species and were on average 6440 U/g in humans, 4340 U/g in the cow, 2660 U/g in the pig, 160 U/g in the dog, 770 U/g in the mouse. There were only moderate differences in the amounts of CuZn-SOD and Mn-SOD. This wide variation in EC-SOD content suggests that the susceptibility to pathologies induced by superoxide radicals in the vascular wall interstitium should vary widely among species.
Extracellular-superoxide dismutase [EC 1.15.1.1] (EC-SOD) is a secretory, tetrameric glycoprotein. A prominent feature of EC-SOD is its affinity for heparin. This enzyme in serum is heterogeneous with regard to heparin-affinity and can be divided into five fractions (I) to (V) by heparin-HPLC, whereas fibroblast-secreted EC-SOD consists mainly of form (V). An intravenous injection of 50 i.u. of heparin/kg body weight into two healthy volunteers led to an immediate rise of serum EC-SOD level by 2.4-2.8-fold. Only form (V), which was a minor component in pre-heparin serum, was increased by the intravenous injection. The half-life of serum EC-SOD after the prompt rise was about 90 min. The in vivo experiment using rats and an in vitro experiment strongly suggested the EC-SOD released into the plasma reconstituted the interaction with glycocalyx on the vascular endothelial cell surface in accordance with the elimination of heparin from the vascular system.
Reactive oxygen metabolites generated from xanthine oxidase play an important role in the pathogenesis of ischemia-induced tissue injury. In a hemorrhagic shock model of ischemia-reperfusion, the intracellular enzyme xanthine oxidase was released into the vasculature. This intravascular source of superoxide (O2.-) and hydrogen peroxide (H2O2) interacted reversibly with glycosaminoglycans of vascular endothelium and markedly concentrated xanthine oxidase at cell surfaces, enhancing its ability to produce extensive damage to remote tissues. Rats were made hypotensive by hemorrhage, maintained for 2h, and reinfused with shed blood. Blood samples were obtained prior to hemorrhage and 15, 30, 60, and 90 min after reperfusion for determination of xanthine oxidase (XO), lactate dehydrogenase (LDH), and alanine transaminase (AST). These enzymes were not significantly elevated in control animals. Reperfusion after hemorrhage-induced ischemia resulted in significantly elevated AST and LDH in both low heparin (100 U/h) and high heparin (1000 U/h) groups. Xanthine oxidase was detected in the circulation only after 90 min reperfusion in the low heparin group and was elevated during the entire reperfusion period in the high heparin group. Studies with cultured vascular endothelium showed significant heparin-reversible binding of XO to cellular glycosaminoglycans. These results suggest that XO can gain access to the circulation following ischemia, where it then binds to the vascular endothelial cells to produce site-specific oxidant injury to organs remote from the site of XO release.
There is evidence that the endothelium plays an important role in the control of human vascular tone by releasing endothelium-derived nitric oxide and, therefore, a defective endothelial function could be involved in the increased peripheral vasoconstriction of patients with chronic congestive heart failure. To investigate endothelial function in humans in vivo, agents such as acetylcholine, a short-acting stimulator of the release of endothelium-derived nitric oxide, has been used. Conversely, N-mono-methyl-L-arginine, a specific inhibitor of nitric oxide synthesis from L-arginine, has recently been shown to decrease blood flow during infusion into the brachial artery of healthy volunteers (control subjects) by inhibiting the basal release of nitric oxide. Consistent with experimental studies, the blood flow response to acetylcholine is blunted in patients with chronic heart failure compared with healthy age-matched volunteers. In contrast, the decrease in blood flow induced by N-mono-methyl-L-arginine appears to be exaggerated in congestive heart failure. The blood flow response to nitroglycerin or sodium nitroprusside, endothelium-independent vasodilators, is usually preserved in patients with chronic, nonedematous heart failure, indicating a normal response of the vascular smooth muscle of resistance vessels to exogenous nitric oxide. In contrast, the dilator response of the radial artery diameter to nitroglycerin and flow-dependent dilation is impaired in patients with chronic heart failure, indicating that the abnormal flow-mediated relaxation of large arteries may be caused by both endothelial and structural abnormalities.(ABSTRACT TRUNCATED AT 250 WORDS)
Much evidence has suggested that the superoxide generated by xanthine oxidase (XOD) within the endothelial cell triggers characteristic free-radical-mediated tissue injuries. Although it has been reported that XOD exists not only in the cytoplasm, but also on the outside surface of the endothelial cell membrane, it is not clear how XOD localizes on the outside of the plasma membrane. Purified human xanthine oxidase (h-XOD) had an affinity for heparin-Sepharose. The binding was largely independent of the pH over the physiological range, whereas it tended to increase at lower pH and to decrease at higher pH. Exposure of h-XOD to the lysine-specific reagent trinitrobenzenesulphonic acid or the arginine-specific reagent phenylglyoxal caused it to lose its affinity for heparin-Sepharose. The binding of h-XOD to heparin is apparently of electrostatic nature, and both lysine and arginine residues are involved in the binding. h-XOD was found to bind to cultured porcine aortic endothelial cells, and this binding was inhibited by the addition of heparin or pretreatment of the cells with heparinase and/or heparitinase. Intravenous injection of heparin into two healthy persons led to a prompt increase in plasma h-XOD concentration. These results suggest that XOD localizes on the outside surface of endothelial cells by association with polysaccharide chains of heparin-like proteoglycans on the endothelial-cell membranes. Superoxide extracellularly generated by XOD may injure the source-endothelial-cell membrane and also attract and activate closely appositional neutrophils, which themselves actually cause progressive oxidative damage.
Chronic heart failure is associated with endothelial dysfunction including impaired endothelium-mediated, flow-dependent dilation (FDD). Since endothelial function is thought to play an important role in coordinating tissue perfusion and modulating arterial compliance, interventions to improve endothelial dysfunction are imperative.
To assess the potential of physical training to restore FDD, 12 patients with chronic heart failure were studied and compared with FDD of 7 age-matched normal subjects. With a recently developed high-resolution ultrasound system, diameters of radial artery were measured at rest, during reactive hyperemia (with increased flow causing endothelium-mediated dilation), and during sodium nitroprusside, causing endothelium-independent dilation. Determination of FDD was repeated after intra-arterial infusion of NG-monomethyl-L-arginine (L-NMMA, 7 mumol/min) to inhibit endothelial synthesis and release of nitric oxide. The protocol was performed at baseline, after 4 weeks of daily handgrip training, and 6 weeks after cessation of the training program. FDD was impaired in heart failure patients compared with normal subjects. L-NMMA attenuated FDD, indicating that the endothelial release of nitric oxide is involved in FDD. Physical training restored FDD in patients with heart failure. In particular, the portion of FDD inhibited by L-NMMA (representing FDD mediated by nitric oxide) was significantly higher after physical training (8-minute occlusion: 8.0 +/- 1% versus 5.4 +/- 0.9%; P < .05; normal subjects: 9.2 +/- 1%).
These results indicate that physical training restores FDD in patients with chronic heart failure, possibly by enhanced endothelial release of nitric oxide.
The endothelium is involved in the control of vascular tone and homeostasis. Risk factors for arteriosclerosis, as well as other conditions have been shown to be associated with a dysfunctional endothelium. Clinically, endothelial function and dysfunction have been mostly evaluated by the assessment of endothelial dependent relaxation, for example in response to acetylcholine or increase inflow. The functional implications of endothelial dysfunction in cardiovascular disease are not well defined, but recent clinical trials have suggested that endothelial dysfunction may affect vascular tone and organ perfusion particularly during stress situations such as exercise. Moreover, endothelial dysfunction may represent an early event in the development of arteriosclerosis. Therefore, recent clinical studies have been performed to restore normal endothelial function in patients, using interventions such as L-arginine, lipid lowering drugs, vitamin C, other antioxidants, or exercise.
The reactions of new spin trap 1-hydroxy-3-carboxy-pyrrolidine (CP-H) with superoxide radicals and peroxynitrite were studied. The rate constants were determined as 3.2 x 10(3) and 4.5 x 10(9) M-1s-1, respectively. It was found that 2mM of spin trap CP-H or 1-hydroxy-2,2,6,6-tetramethyl-4-oxo-piperidine (TEMPONE-H) provide almost the same spin trapping efficacy. In contrast to TEMPONE-H the reaction of CP-H with peroxynitrite was inhibited by 20 mM DMSO. This simplifies the quantification of peroxynitrite formation. During the reaction of CP-H and TEMPONE-H with superoxide radicals or peroxynitrite the stable nitroxide radicals 3-carboxy-proxyl (CP) and 2,2,6,6-tetramethyl-4-oxo-piperidinoxyl (TEMPONE) are formed. It was found that the rate of reduction of CP by glutathione or by smooth muscle cells was two-fold slower and the reduction of CP by ascorbate was 66-fold slower than corresponding rates of reduction of TEMPONE. Therefore quantification of the formation of superoxide radicals and of peroxynitrite by CP-H is much less hindered by a variety of biological reductants than in case of TEMPONE-H. Thus, CP-H is more suitable for spin trapping of superoxide radicals and peroxynitrite in biological systems than the TEMPONE-H.
Chronic heart failure (CHF) is associated with endothelial dysfunction including impaired endothelium-mediated, flow-dependent dilation (FDD). There is evidence for increased radical formation in CHF, raising the possibility that nitric oxide is inactivated by radicals, thereby impairing endothelial function. To test this hypothesis, we determined the effect of the antioxidant vitamin C on FDD in patients with CHF.
High-resolution ultrasound and Doppler was used to measure radial artery diameter and blood flow in 15 patients with CHF and 8 healthy volunteers. Vascular effects of vitamin C (25 mg/min IA) and placebo were determined at rest and during reactive hyperemia (causing endothelium-mediated dilation) before and after intra-arterial infusion of N-monomethyl-L-arginine (L-NMMA) to inhibit endothelial synthesis of nitric oxide. Vitamin C restored FDD in patients with heart failure after acute intra-arterial administration (13.2+/-1.7% versus 8.2+/-1.0%; P<.01) and after 4 weeks of oral therapy (11.9+/-0.9% versus 8.2+/-1.0%; P<.05). In particular, the portion of FDD mediated by nitric oxide (ie, inhibited by L-NMMA) was increased after acute as well as after chronic treatment (CHF baseline: 4.2+/-0.7%; acute: 9.1+/-1.3%; chronic: 7.3+/-1.2%; normal subjects: 8.9+/-0.8%; P<.01).
Vitamin C improves FDD in patients with CHF as the result of increased availability of nitric oxide. This observation supports the concept that endothelial dysfunction in patients with CHF is, at least in part, due to accelerated degradation of nitric oxide by radicals.
Subcellular localisation of xanthine oxidoreductase (XOR) was determined by indirect immunofluorescence using confocal microscopy in human endothelial and epithelial cell lines and in primary cultures of human umbilical vein endothelial cells. XOR was diffusely distributed throughout the cytoplasm but with higher intensity in the perinuclear region. In non-permeabilised cells, XOR was clearly seen to be asymmetrically located on the outer surfaces, showing, in many cases, a higher intensity on those faces apposed by closely neighbouring cells. Such specific distribution suggests a functional role for the enzyme in cell-cell interactions, possibly involving signalling via reactive oxygen species.
Reactive oxygen metabolites generated from endothelial xanthine oxidase (XO) trigger reperfusion injury in many organs. We evaluated the possibility that endothelial XO was localized on the endothelial cell surface, as well as within the cytoplasm.
Primary cultures of bovine (BAECs) and porcine (PAECs) aortic endothelial cells were grown in media documented to be free of XO. Polyclonal and monoclonal antibodies were developed against XO. These antibodies were used to evaluate BAEC and PAEC for cell surface XO through immunofluorescence staining, hybridoma cell surface labeling, and endothelial cell surface binding.
These antibodies bound specifically to the surface of these cells when the membrane was shown to be intact and impermeable (and the cytoplasm inaccessible) to immunoglobulins Moreover, hybridoma cells expressing monoclonal antibody to XO bound specifically to the endothelial cell surface. Finally, intact endothelial cells bound specifically to the anti-XO polyclonal antibodies immobilized to the surface of a Petri dish. The integrity of these endothelial cell plasma membranes was demonstrated by the subsequent growth and replication of these cells in culture.
These findings indicate that XO is present on the outside surface of the endothelial cell plasma membrane. This would not only explain the known in vivo efficacy of intravascularly administered large molecular weight antioxidants (such as superoxide dismutase) but could have important implications for inflammatory signaling.
The purpose of this study was to determine the effects of systemic exercise training on endothelium-mediated arteriolar vasodilation of the lower limb and its relation to exercise capacity in chronic heart failure (CHF). Endothelial dysfunction is a key feature of CHF, contributing to increased peripheral vasoconstriction and impaired exercise capacity. Local handgrip exercise has previously been shown to enhance endothelium-dependent vasodilation in conduit and resistance vessels in CHF.
Twenty patients were prospectively randomized to a training group (n=10, left ventricular ejection fraction [LVEF] 24+/-4%) or a control group (n=10, LVEF 23+/-3%). At baseline and after 6 months, peak flow velocity was measured in the left femoral artery using a Doppler wire; vessel diameter was determined by quantitative angiography. Peripheral blood flow was calculated from average peak velocity (APV) and arterial cross-sectional area. After exercise training, nitroglycerin-induced endothelium-independent vasodilation remained unaltered (271% versus 281%, P=NS). Peripheral blood flow improved significantly in response to 90 microg/min acetylcholine by 203% (from 152+/-79 to 461+/-104 mL/min, P<0.05 versus control group) and the inhibiting effect of L-NMMA increased by 174% (from -46+/-25 to -126+/-19 mL/min, P<0.05 versus control group). Peak oxygen uptake increased by 26% (P<0.01 versus control group). The increase in peak oxygen uptake was correlated with the endothelium-dependent change in peripheral blood flow (r=0.64, P<0. 005).
Regular physical exercise improves both basal endothelial nitric oxide (NO) formation and agonist-mediated endothelium-dependent vasodilation of the skeletal muscle vasculature in patients with CHF. The correction of endothelium dysfunction is associated with a significant increase in exercise capacity.
Patients with chronic heart failure are characterized by systemic vasoconstriction and reduced peripheral perfusion, which are thought to contribute to the impaired exercise capacity in this disorder. Whereas an increased sympathetic tone and an activated renin-angiotensin system have been proposed to be involved in the reduced vasodilator capacity in heart failure, the important role of the endothelium in coordinating tissue perfusion has not been recognized until recently. Recent clinical studies have documented impaired endothelium-dependent relaxations of peripheral resistance and conduit arteries in patients with chronic heart failure, most likely due to impaired availability of nitric oxide (NO). On the other hand, the endothelial production of vasoconstricting factors1 such as angiotensin II or endothelin appears to be increased in severe heart failure. Whereas numerous important functions of the endothelium have been recognized in the past, many recent experimental and clinical studies have focused on endothelium-derived NO, probably because one of its main functions, vascular relaxation, can easily be assessed in humans in vivo. NO is a potent endogenous vasodilator and appears to be responsible for the maintenance of basal vascular tone; it is also thought to exert other important effects, such as inhibition/modulation of platelet aggregation, leukocyte adhesion, cell respiration, and apoptosis. The mechanisms of the actions of NO include activation of second messengers such as cGMP, direct effects on redox-sensitive regulatory proteins, and interactions with reactive oxygen species.
Impaired endothelium-dependent vascular relaxation has been documented in virtually all cardiovascular disorders and appears to occur early in the course of cardiovascular disorders such as arteriosclerosis, diabetes mellitus, hypercholesterolemia, or hypertension. Impaired endothelium-dependent relaxation may be associated with alterations of other endothelial functions, such as adhesion of leukocytes or altered balance of profibrinolytic to prothrombotic activity; however, whether or not impaired endothelium-dependent relaxation always reflects a more general “endothelium dysfunction” remains …
Endothelial dysfunction of the peripheral vasculature is a well-known phenomenon in congestive heart failure that contributes to the elevated peripheral resistance; however, the underlying mechanisms have not yet been clarified.
Dilator responses, the expression of protein and mRNA of the endothelial nitric oxide synthase (eNOS), inducible NOS (iNOS), and soluble guanylate cyclase (sGC), and superoxide anion (O(2)(-)) and peroxynitrite production were determined in aortic rings from Wistar rats 8 weeks after myocardial infarction and compared with those in sham-operated animals. In rats with heart failure, the concentration-response curve of the endothelium-dependent vasodilator acetylcholine (after preconstriction with phenylephrine) was significantly shifted to the right, and the maximum relaxation was attenuated. Determination of expression levels of the 2 key enzymes for NO-mediated dilations, eNOS and sGC, revealed a marked upregulation of both enzymes in aortas from rats with heart failure, whereas iNOS expression was not changed. Pretreatment with exogenous superoxide dismutase partially restored the acetylcholine-induced relaxation in aortas from rats with heart failure. Aortic basal and NADH-stimulated O(2)(-) production assessed by use of lucigenin-enhanced chemiluminescence was significantly elevated in rats with chronic myocardial infarction. Peroxynitrite-mediated nitration of protein tyrosine residues was not different between the 2 groups of rats.
These results demonstrate that endothelial dysfunction in ischemic heart failure occurs despite an enhanced vascular eNOS and sGC expression and can be attributed to an increase in vascular O(2)(-) production by an NADH-dependent oxidase. By inactivation of NO, O(2)(-) production appears to be an essential mechanism for the endothelial dysfunction observed in heart failure.
Glyceryl trinitrate (GTN) and pentaerythrityl tetranitrate (PETN) are among the most known organic nitrates that are used in cardiovascular therapy as vasodilators. However, anti-ischemic therapy with organic nitrates is complicated by the induction of nitrate tolerance. When nitrates are metabolized to release nitric oxide (NO), there is considerable coproduction of superoxide radicals in vessels leading to inactivation of NO. However, nitrate-induced increase of superoxide radical formation in vivo has not been reported. In this work, the authors studied the in vivo formation of superoxide radicals induced by treatment with PETN or GTN and determined the antioxidant effect of vitamin C. The formation of superoxide radicals was determined by the oxidation of 1-hydroxy-3-carboxy-pyrrolidine (CP-H) to paramagnetic 3-carboxy-proxyl (CP) using electron spin resonance spectroscopy. CP-H (9 mg/kg intravenous bolus and 0.225 mg/kg per minute continuous intravenous GTN or PETN 130 microg/kg) were infused into anesthetized rabbits. Every 5 min, blood samples were obtained from Arteria carotis to measure the CP formation. Both PETN and GTN showed similar vasodilator effects. Formation of CP in blood after infusions of GTN and PETN were 2.0+/-0.4 microM and 0.98+/-0.23 microM, respectively. Pretreatment with 30 mg/kg vitamin C led to a significant decrease in CP formation: 0.27+/-0.14 microM (vitamin C plus GTN) and 0.34+/-0.15 microM (vitamin C plus PETN). Pretreatment of animals with superoxide dismutase (15,000 units/kg) significantly inhibited nitrate-induced nitroxide formation. Therefore, in vivo infusion of GTN or PETN in rabbits increased the formation of superoxide radicals in the vasculature. PETN provoked a minimal stimulation of superoxide radical formation without simultaneous development of nitrate tolerance. The data suggest that the formation of superoxide radicals induced by organic nitrate correlates with the development of nitrate tolerance. The effect of vitamin C on CP formation leads to the conclusion that vitamin C can be used as an effective antioxidant for protection against nitrate-induced superoxide radical formation in vivo.
Allopurinol, an inhibitor of xanthine oxidase, increases myofilament calcium responsiveness and blunts calcium cycling in isolated cardiac muscle. We sought to extend these observations to conscious dogs with and without pacing-induced heart failure and tested the prediction that allopurinol would have a positive inotropic effect without increasing energy expenditure, thereby increasing mechanical efficiency. In control dogs (n=10), allopurinol (200 mg IV) caused a small positive inotropic effect; (dP/dt)(max) increased from 3103+/-162 to 3373+/-225 mm Hg/s (+8.3+/-3.2%; P=0.01), but preload-recruitable stroke work and ventricular elastance did not change. In heart failure (n=5), this effect was larger; (dP/dt)(max) rose from 1602+/-190 to 1988+/-251 mm Hg/s (+24.4+/-8.7%; P=0.03), preload-recruitable stroke work increased from 55.8+/-9.1 to 84. 9+/-12.2 mm Hg (+28.1+/-5.3%; P=0.02), and ventricular elastance rose from 6.0+/-1.6 to 10.5+/-2.2 mm Hg/mm (P=0.03). Allopurinol did not affect myocardial lusitropic properties either in control or heart failure dogs. In heart failure dogs, but not controls, allopurinol decreased myocardial oxygen consumption (-49+/-4.6%; P=0. 002) and substantially increased mechanical efficiency (stroke work/myocardial oxygen consumption; +122+/-42%; P=0.04). Moreover, xanthine oxidase activity was approximately 4-fold increased in failing versus control dog hearts (387+/-125 versus 78+/-72 pmol/min. mg(-1); P=0.04) but was not detectable in plasma. These data indicate that allopurinol possesses unique inotropic properties, increasing myocardial contractility while simultaneously reducing cardiac energy requirements. The resultant boost in myocardial contractile efficiency may prove beneficial in the treatment of congestive heart failure.
Background:
Increased vascular superoxide anion (.O(2)(-)) production contributes to endothelial dysfunction and hypertension in animal models of cardiovascular disease. Observations in experimental animals suggest that angiotensin II (Ang II) increases.O(2)(-) production by activation of vascular NAD(P)H oxidase. We studied the sources of.O(2)(-) production in human blood vessels and investigated whether, and by what mechanism, Ang II might alter vascular.O(2)(-) production.
Methods and results:
Internal mammary arteries (IMAs) and saphenous veins (SVs) were collected at the time of cardiac surgery. Vessels were incubated in Krebs buffer at 37 degrees C.O(2)(-) was measured by lucigenin chemiluminescence. Basal. O(2)(-) concentrations were greater in IMAs than SVs. Inhibitors of NAD(P)H oxidase (10 micromol/L to 200 micromol/L diphenyleneiodonium) and xanthine oxidase (1 mmol/L allopurinol) caused reductions in.O(2)(-) concentrations in both IMAs and SVs. Western blotting of superoxide dismutase proteins demonstrated similar expression in IMAs and SVs. Vessels were also incubated in the presence or absence of Ang II (1 pmol/L to 1 micromol/L). Ang II increased.O(2)(-) production in IMAs at 4 hours of incubation (control, 978+/-117 pmol. min(-1). mg(-1); 1 micromol/L of Ang II, 1690+/-213 pmol. min(-1). mg(-1); n=27, P=0.0001, 95% CI 336, 925) but not in SVs. This effect was completely inhibited by coincubation of IMAs with DPI (100 micromol/L), a nonspecific Ang II antagonist ([sar(1), thre(8)]-Ang II, 1 micromol/L) and a specific Ang II type 1 (AT(1)) receptor antagonist (losartan, 1 micromol/L). Conclusions-. O(2)(-) production is greater in human IMAs than in SVs. NAD(P)H oxidase and xanthine oxidase are sources of.O(2)(-) production in these vessels. The vasoactive peptide Ang II increases.O(2)(-) production in human arteries by an AT(1) receptor-dependent mechanism.
Oxygen free radicals as well as immunological reactions have been suggested to play important roles in atherogenesis and other pathological processes of the blood vessel wall. We have previously shown that the vascular wall contains exceptionally large amounts of extracellular superoxide dismutase (EC-SOD) and that the enzyme is produced and secreted to the extracellular space by the smooth muscle cells. In this work, we studied the influence of inflammatory cytokines on vascular smooth muscle cell expression of EC-SOD, the mitochondrial manganese superoxide dismutase (Mn-SOD) and the cytosolic copper zinc superoxide dismutase (CuZn-SOD). The expression of EC-SOD was up-regulated by interferon-gamma (IFN-gamma) and interleukin 4 (IL-4). and was down-regulated by tumor necrosis factor-alpha (TNF-alpha). The ratio between the maximal stimulation and depression observed was around 20-fold. The responses were slow and developed over periods of several days. The Mn-SOD activity was strongly up-regulated by TNF-alpha and IL-1alpha and moderately by IFN-gamma. The CuZn-SOD activity of the smooth muscle cells was not significantly influenced by any of the cytokines. The findings suggest that large changes in the SOD isoenzymes might occur in vascular diseases, significantly altering the susceptibility of the vascular wall to adverse effects of the superoxide radical.
The molecular basis for heart failure is unknown, but oxidative stress is associated with the pathogenesis of the disease. We tested the hypothesis that the activity of xanthine oxidoreductase (XOR), a free-radical generating enzyme, increases in hypertrophied and failing heart. We studied XOR in two rat models: (1) The monocrotaline-induced right ventricular hypertrophy and failure model; (2) coronary artery ligation induced heart failure, with left ventricular failure and compensatory right ventricular hypertrophy at different stages at 3 and 8 weeks post-infarction, respectively. XOR activity was measured at 30 degrees C and the reaction products were analysed by HPLC. In both models XOR activity in hypertrophic and control ventricles was similar. In the monocrotaline model, the hearts showed enhanced XOR activity in the failing right ventricle (65+/-5 mU/g w/w), as compared to that in the unaffected left ventricle (47+/-3 mU/g P<0.05, n=6-7). In the coronary ligation model, XOR activities did not differ at 3 and 8 weeks. In the infarcted left ventricle, XOR activity increased from 29.4+/-1.4 mU/g (n=6) in sham-operated rats, to 48+/-3 and 80+/-6 mU/g (n=8 P<0.05 v sham) in the viable and infarcted parts of failing rat hearts, respectively. With affinity-purified polyclonal antibody, XOR was localized in CD68+ inflammatory cells of which the number increased more in the failing than in sham-operated hearts. Our results show that the expression of functional XOR is elevated in failing but not in hypertrophic ventricles, suggesting its potential role in the transition from cardiac hypertrophy into failure.
Endothelium-derived NO is considered to be primarily an important determinant of vascular tone and platelet activity; however, the modulation of myocardial metabolism by NO may be one of its most important roles. This modulation may be critical for the regulation of tissue metabolism. Several physiological processes act in concert to make endothelial NO synthase-derived NO potentially important in the regulation of mitochondrial respiration in cardiac tissue, including (1) the nature of the capillary network in the myocardium, (2) the diffusion distance for NO, (3) the low toxicity of NO at physiological (nanomolar) concentrations, (4) the fact that low PO(2) in tissue facilitates the action of NO on cytochrome oxidase, and (5) the formation of oxygen free radicals. A decrease in NO production is involved in the pathophysiological modifications that occur in heart failure and diabetes, disease states associated with altered cardiac metabolism that contributes to the evolution of the disease process. In contrast, several drugs (eg, angiotensin-converting enzyme inhibitors, amlodipine, and statins) can restore or maintain endogenous production of NO by endothelial cells, and this mechanism may explain part of their therapeutic efficiency. Thus, the purpose of this review is to critically evaluate the role of NO in the control of mitochondrial respiration, with special emphasis on its effect on cardiac metabolism.
We examined whether xanthine oxidoreductase (XOR), a hypoxia-inducible enzyme capable of generating reactive oxygen species, is involved in the onset of angiotensin (Ang) II-induced vascular dysfunction in double-transgenic rats (dTGR) harboring human renin and human angiotensinogen genes. In 7-week-old hypertensive dTGR, the endothelium-mediated relaxation of noradrenaline (NA)-precontracted renal arterial rings to acetylcholine (ACh) in vitro was markedly impaired compared with Sprague Dawley rats. Preincubation with superoxide dismutase (SOD) improved the endothelium-dependent vascular relaxation, indicating that in dTGR, endothelial dysfunction is associated with increased superoxide formation. Preincubation with the XOR inhibitor oxypurinol also improved endothelium-dependent vascular relaxation. The endothelium-independent relaxation to sodium nitroprusside was similar in both strains. In dTGR, serum 8-isoprostaglandin F(2alpha), a vasoconstrictor and antinatriuretic arachidonic acid metabolite produced by oxidative stress, was increased by 100%, and the activity of XOR in the kidney was increased by 40%. Urinary nitrate plus nitrite (NO(x)) excretion, a marker of total body NO generation, was decreased by 85%. Contractile responses of renal arteries to Ang II, endothelin-1 (ET-1), and NA were decreased in dTGR, suggesting hypertension-associated generalized changes in the vascular function rather than a receptor-specific desensitization. Valsartan (30 mg/kg PO for 3 weeks) normalized blood pressure, endothelial dysfunction, and the contractile responses to ET-1 and NA. Valsartan also normalized serum 8-isoprostaglandin F(2alpha) levels, renal XOR activity, and, to a degree, NO(x) excretion. Thus, overproduction of Ang II in dTGR induces pronounced endothelial dysfunction, whereas the sensitivity of vascular smooth muscle cells to nitric oxide is unaltered. Ang II-induced endothelial dysfunction is associated with increased oxidative stress and vascular xanthine oxidase activity.