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Role of endothelin-1 in hypertension
Abstract
Endothelin-1 (ET-1) was first characterized as a potent vasoconstrictor and is overexpressed in the vasculature in different models of hypertension, such as deoxycorticosterone acetate-salt rats, Dahl salt-sensitive rats, and stroke-prone spontaneously hypertensive rats. Moreover, patients with moderate to severe hypertension present increased vascular levels of prepro-ET-1 mRNA. In addition to their blood pressure-lowering effects, ET receptor antagonists are able to reduce vascular growth. Recent data suggest the involvement of an inflammatory response in the effects of ET-1, which contributes to vascular remodeling and endothelial dysfunction. Increasing evidence underscores the potential therapeutic benefit of ET receptor antagonists in different hypertension-related complications, not only in essential hypertension, but also in patients with type 2 diabetes.
... Based on the accumulating data from experimental and clinical studies, it can be assumed that there is a link between the increased biological activity of ET-1 and the development of HTN [44,[55][56][57][58]. Probably, ET-1 is causally related to high BP through synergistic interactions of the following mechanisms: (1) participation in the development of oxidative stress and low-grade inflammation in the vascular wall with the occurrence of ED; (2) participation in the pathogenesis of arterial stiffness; (3) participation in the processes of arterial remodeling; (4) participation in the mechanisms regulating BP. ...
... A number of experimental and clinical studies have shown that ET-1 is responsible for maintaining arterial stiffness [27,91,92]. In ED, where the production of NO is reduced and that of ET-1 is increased, the balance is changed to increase arterial stiffness [57]. Arteriosclerosis [93][94][95] and its most common form, atherosclerosis [96][97][98], are the main pathological processes associated with increased hardness of the arteries (Figure 3). ...
Hypertension (HTN) is one of the most prevalent diseases worldwide and is among the most important risk factors for cardiovascular and cerebrovascular complications. It is currently thought to be the result of disturbances in a number of neural, renal, hormonal, and vascular mechanisms regulating blood pressure (BP), so crucial importance is given to the imbalance of a number of vasoactive factors produced by the endothelium. Decreased nitric oxide production and increased production of endothelin-1 (ET-1) in the vascular wall may promote oxidative stress and low-grade inflammation, with the development of endothelial dysfunction (ED) and increased vasoconstric-tor activity. Increased ET-1 production can contribute to arterial aging and the development of atherosclerotic changes, which are associated with increased arterial stiffness and manifestation of isolated systolic HTN. In addition, ET-1 is involved in the complex regulation of BP through syner-gistic interactions with angiotensin II, regulates the production of catecholamines and sympathetic activity, affects renal hemodynamics and water-salt balance, and regulates baroreceptor activity and myocardial contractility. This review focuses on the relationship between ET-1 and HTN and in particular on the key role of ET-1 in the pathogenesis of ED, arterial structural changes, and impaired vascular regulation of BP. The information presented includes basic concepts on the role of ET-1 in the pathogenesis of HTN without going into detailed analyses, which allows it to be used by a wide range of specialists. Also, the main pathological processes and mechanisms are richly illustrated for better understanding.
... Moreover, some reports indicated that ET-1 might amplify other vasoconstrictors reflexes leading to vast pathophysiological consequence even at low plasma concentrations. This conclusion came from the potentiation of contractile responses of human arteries in response to catecholamines and serotonin by the addition of subthreshold concentrations of ET-1 [61][62][63][64]. ET-1 is thought to have a pro-arrhythmogenic effect and a pathophysiological role in the progression of ischemia /reperfusion and myocardial and vascular remodeling based on its ability to stimulate vascular smooth muscle proliferation and cardiac hypertrophy [65]. ...
... This potent vasoconstrictor peptide also reveals a vital role in several other cardiovascular illnesses [5,16,18,20]. These are hypertension [59][60][61][62][63], coronary vasospasm [64] unstable angina [65], myocardial infarction [70], cardiac insufficiency [71], atherosclerosis [72,73], and cerebral vasospasm associated with subarachnoid haemorrhage [74]. ET-1 also plays role in other related diseases and pathophysiological status like Raynaud's disease [75], migraine [76,77], inflammatory pain and cutaneous inflammation [78], platelet aggregation [79], diabetes and obesity [80][81][82][83], autoimmune diseases and transplantation rejection [84], tumour cell proliferation and invasion [85]. ...
Endothelin-1, (ET-1, EDN1) is endogenous polypeptide demonstrates dominant vasoconstriction activity and mitogenic effect, on the heart it has positive inotropic and chronotropic properties, stimulates the sympathetic and the renin-angiotensin-aldosterone systems and modify homeostasis. The human ET-1 gene which consists of 6836 nucleotides located on chromosome 6p23-p24 produces Pre-pro-ET-1, which consequently cleaved to big-ET-1. The mature 21-amino acid ET-1 is generated by subsequent enzymatic cleavage of the big-ET-1. A comprehensive review of the literature on the consequences of different ET-1 gene variants on ET-1 linked diseases not accomplished. Many variants of ET-1 gene, including transversion, transition, insertion, and repeated nucleotide polymorphisms, which influences the hereditary risk of cardiovascular and other related diseases have already been located, genotyped, and examined. Among them ten polymorphisms which are transversion; -1370 (T-1370G) (rs1800541), +5665 (Lys198Asn) (rs5370), G2288T polymorphisms (rs2070699), and -974 C>A (rs3087459) polymorphism, transition; +3660 (Glu106Glu) (rs5369), G(8002)A (rs2071942), rs1476046 polymorphism , rs2071943 polymorphism, and rs9296345 polymorphism, and insertion/delete; +138 (+138/ex1ins/delA) (rs1800997) were studied and phenotyped extensively. Some significant association with many different diseases (phenotypes) especially those related to cardiovascular system diseases such as hypertension, ischemic diseases, angina, and acute coronary syndrome have been described in the literature. Some are associated with other diseases such as asthma, pulmonary edema, hearing impairment, obesity and sleep apnea. Moreover, some are modifying the course and adverse effects of several drugs. Many of these polymorphisms were studied about each other, thus; some inner complex association manner also described.
... It has been found that the vasoconstrictor activity of ET-1 increases in the elderly (Guilder et al. 2007;Thijssen et al. 2007), and that the synthesis of ET-1 is greater in cultured aortic endothelial cells obtained from older compared with younger donors (Tokunaga et al. 1992;Seals et al. 2011). Based on the accumulating data from experimental and clinical studies, it can be assumed that there is a link between the increased biological activity of ET-1 and the development of hypertension (Pinto-Sietsma & Paul 1998;Iglarz & Schiffrin 2003;del Villar et al. 2005;Rahman et al. 2015;Kostov et al. 2016). Probably, ET-1 is causally related to high BP through synergistic interactions of the following mechanisms: (1) participation in the development of oxidative stress and low-grade inflammation in the vascular wall with the occurrence of ED; ...
... К его главному эффекту относят влияние на гладкие мышцы сосудов, в частности вазоконстрикцию, активацию митогенеза, пролиферацию клеток и фиброз интимы с повышением жесткости сосудов [16]. С учетом его выраженного вазоконстрикторного действия эндотелин-1 рассматривается в качестве одной из важнейших причин артериальной гипертензии [17] и острой ишемии миокарда [18,19]. ...
Objective. To study the state of endothelial function in children with familial hypercholesterolemia by evaluating the flow-dependent vasodilation of the brachial artery and serum nitric oxide and endothelin-1 levels.Children characteristics and research methods. The study included total 62 children: 30 children (mean age 10,3 years ± 2,8) with a heterozygous form of familial hypercholesterolemia, not taking lipid-lowering therapy (main group), and 32 healthy children (mean age 10,3 years ± 2,8) in the control group. The content of endothelin-1 and nitric oxide in blood serum were determined by enzyme immunoassay. Flow-dependent vasodilation of brachial artery was measured using Philips Affinity 70 (Release 3,0.3, Philips Healthcare, USA).Results. The analysis of endothelin-1 level did not reveal statistically significant differences between healthy children and patients with familial hypercholesterolemia (0,213 [0,012; 0,368] and 0,227 [0,15; 0,315] pmol/l accordingly; p=0,062). The level of nitrogen oxide in healthy children was 33,6 [20—51] pmol/l, while patients with familial hypercholesterolemia had statistically significantly higher level of nitrogen oxide — 103,7 [48—152] pmol/l, p=0,001). Flow-dependent brachial artery vasodilation in healthy children was 9,82 [7,8; 11,2]% and in patients with familial hypercholesterolemia this indicator was decreased — 9,46 [6,5; 10,8]% (p=0,742).Conclusion. A study of endothelial function in children with familial hypercholesterolemia aged 7—11 years revealed an increase in the concentration of nitrogen oxide relative to healthy patients, probably of a compensatory nature. The flow-dependent vasodilation of the brachial artery and the level of endothelin-1 did not significantly differ from the control group. Due to possible cumulative effect of low-density proteins, it is necessary to monitor endothelial function in children with familial hypercholesterolemia in dynamics.
... In this case report, the patient exhibited two of the three most common paraneoplastic syndromes associated with renal cell carcinoma: polycythemia and hypertension. Although several mechanisms have been proposed to explain hypertension in renal cell carcinoma patients, current studies suggest that the vasoactive peptides endothelin-1, urotensin-II, and adrenomedullin are likely to be involved [12][13][14][15][16][17][18]. Furthermore, polycythemia also contributes to hypertension through the upregulation of hypoxia inducible factor-1 (HIF-1) from renal cancer and epithelial cells increasing EPO production [19][20][21]. ...
A 61-year-old obese Caucasian male with past medical history of smoking, hypertension, chronic obstructive pulmonary disease (COPD), and sleep apnea presented to the hematology clinic with polycythemia. Despite the newly-diagnosed polycythemia, the patient denied any significant symptoms or history of blood clots. Further evaluation with computerized tomography (CT) and ultrasound showed a large renal mass suspicious for renal cell carcinoma of the right kidney. An incidental abdominal aortic aneurysm (AAA) measuring was also appreciated on imaging. Subsequent histological sections of the tumor showed cell renal cell carcinoma. Though previously reported, the concomitant finding of an AAA with renal cell carcinoma with a normal erythropoietin levels is surprising. Given the surgical complications associated with concomitant conditions with renal cell carcinoma, further investigation into paraneoplastic syndromes secondary to renal cell carcinoma remains open to investigation.
... Aberrant increases in the plasma levels of vasoactive peptides are a hallmark of these vascular diseases. The involvement of the vasoconstrictor endothelin-1 (ET-1) in the activation of signaling events intimately linked to the migration and proliferation of VSMCs has been documented over the past years (3,4). In VSMCs, ET-1 exerts its growth-promoting effects through the activation of its seven transmembrane domain guanine nucleotide-binding protein (G protein)coupled receptor (GPCR) (5), ETA receptor. ...
We have previously demonstrated that the non-receptor protein tyrosine kinase (NR-PTK) c-Src is an upstream regulator of endothelin-1 (ET-1) and angiotensin II-induced activation of protein kinase B (PKB) signaling in vascular smooth muscle cells (VSMCs). We have also demonstrated that ET-1 potently induces the expression of the early growth response protein-1 (Egr-1), a zinc finger transcription factor that is overexpressed in models of vascular diseases, such as atherosclerosis. However, the involvement of c-Src in ET-1‑induced Egr-1 expression has not yet been investigated and its role in mitogen-activated protein kinase (MAPK) signaling remains controversial. Therefore, the aim of the present study was to examine the role of c-Src in the ET-1-induced phosphorylation of extracellular signal-regulated kinase (ERK)1/2, c-Jun N-terminal kinase (JNK) and p38 MAPK, 3 key members of the MAPK family and in the regulation of Egr-1 expression in rat aortic A10 VSMCs. ET-1 rapidly induced the phosphorylation of MAPKs, as well as the expression of Egr-1; however, treatment of the VSMCs with PP2, a specific pharmacological inhibitor of c-Src, dose-dependently reduced the phosphorylation of the 3 MAPKs and the expression of Egr-1 induced by ET-1. Furthermore, in mouse embryonic fibroblasts (MEFs) deficient in c-Src (SYF), the ET-1-induced Egr-1 expression and MAPK phosphorylation were significantly suppressed, as compared to MEFs expressing normal Src levels. These results suggest that c-Src plays a critical role in mediating ET-1-induced MAPK phosphorylation and Egr-1 expression in VSMCs.
The antihypertensive effect of wine lees powder (WLPW) from a Cabernet grape variety was related to its high content in flavanols and anthocyanins compounds. This study investigates the involvement of endothelial-derived factors and SIRT1 in its bioactivity. Spontaneously hypertensive rats (SHR) were orally administered water or WLPW (125 mg/kg bw). Posteriorly, both groups were intraperitoneally administered saline, Nω-nitro-L-arginine methyl ester (L-NAME), a nitric oxide (NO) synthesis inhibitor, indomethacin, a prostacyclin synthesis inhibitor, or sirtinol, an inhibitor of sirtuins. Blood pressure (BP) was recorded before and 6 h after WLPW administration. In an additional experiment, SHR were administered water or WLPW and endothelial expressions of eNos, Sirt1, Nox4, and Et1 were determined. The BP-lowering properties of WLPW were abolished by L-NAME and partially reduced by indomethacin, demonstrating that WLPW antihypertensive effect was mediated by changes in NO availability, although prostacyclin also contributed to this activity. Moreover, BP-lowering effect was reduced by sirtinol, indicating that WLPW decreased BP in a SIRT1-dependent manner. Furthermore, WLPW upregulated eNos and Sirt1 and downregulated Nox4 and Et1 endothelial gene expression. These results evidence the vasoprotective effect of WLPW and show that its antihypertensive effect in SHR is endothelium dependent and mediated by SIRT1.
Context.—Studies have demonstrated that high serum leptin levels are associated with aging. However, we do not know whether hyperleptinemia is a relevant risk factor for high blood pressure (HBP) in the elderly.
Objective.—To determine the relationship between hyperleptinemia and HBP in the elderly.
Design.—A comparative cross-sectional study was carried out in a convenience sample of 70 healthy elderly persons comprising 46 women (mean age, 67 ± 5.8 years) and 24 men (mean age, 73 ± 7.5 years), and a group of 91 elderly persons with HBP, comprising 62 women (mean age, 67 ± 8.2 years) and 29 men (mean age, 70 ± 0.3 years). We measured serum leptin levels through the radioimmunoassay method.
Results.—The elderly subjects with HBP had significantly higher leptin levels than the healthy elderly subjects (P = .02). Furthermore, in female elderly subjects we observed a statistically significant correlation between systolic blood pressure and leptin (r = 0.37, P = .003), as well as systolic blood pressure and age (r = 0.29, P = .02), but not with diastolic blood pressure. In male elderly subjects, there was no correlation between leptin and systolic blood pressure or leptin and diastolic blood pressure. However, hyperleptinemia as risk factor for HBP was nearly 5 times higher in men than in women (men, odds ratio = 18.0, 95% confidence interval 3.2–100.9, P < .001 vs women, odds ratio = 3.33, 95% confidence interval 1.4–7.4, P = .003).
Conclusions.—Our data suggest that hyperleptinemia was a significant risk factor for HBP elderly individuals, mainly in men.
Objective:
In the present study, we used a two-kidney-two-clip (2k2c) stroke-prone renovascular hypertension rat model (RHRSP) to investigate the protective effects of ligustrazine (TMP) on cerebral arteries and to examine PI3K/Akt pathway behavior under this protection.
Methods:
The cerebral artery remodeling was induced by 2k2c-induced renovascular hypertension. Brain basilar artery tissues were isolated and their histological changes were detected through H&E and EVG staining, α-SMA IHC staining, and transmission electron microscopy at four, eight, and twelve weeks after 2k2c surgery, both with and without TMP treatment. Meanwhile, the ET-1, Ang II, and NO levels in basilar arteries and plasma were determined. Furthermore, the PTEN expression and the activation of PI3K/Akt in basilar artery tissues were detected through IHC and Western Blot. In addition, the primary basilar artery smooth muscle cells (BASMCs) were cultured and TMP protection of BASMCs stimulated with ET-1/Ang II in the presence or absence of insulin-like growth factor 1 (IGF-1) was determined.
Results:
TMP attenuated basilar artery remodeling, decreased ET-1 and Ang II levels and increased NO level in basilar arteries and plasma of RHRSP rats. Moreover, TMP reduced BASMCs proliferation upon ET-1/Ang II stimulation. We also found that TMP could effectively suppress the activation of PI3K/Akt in 2k2c-RHRSP rat basilar artery and ET-1/Ang II stimulated BASMCs. Most importantly, IGF-1, as an activator of PI3K/Akt, could damage the protective effect of TMP.
Conclusions:
TMP exerts its protective effects and prevents basilar artery remodeling in RHRSP rats at least partly through the inhibition of PI3K/Akt pathway.
One of the most fundamental principles of circulatory function is the ability of each tissue to control its own local blood flow in proportion to its metabolic needs.
What are some of the specific needs of the tissues for blood flow? The answer to this is many-fold, including the following:
1. Delivery of oxygen to the tissues
2. Delivery of other nutrients, such as glucose, amino acids, and fatty acids
3. Removal of carbon dioxide from the tissues
4. Removal of hydrogen ions from the tissues
5. Maintenance of proper concentrations of other ions in the tissues
6. Transport of various hormones and other substances to the different tissues
Certain organs have special requirements. For instance, blood flow to the skin determines heat loss from the body and in this way helps to control body temperature. Also, delivery of adequate quantities of blood plasma to the kidneys allows the kidneys to excrete the waste products of the body.
We shall see that most of these factors exert extreme degrees of local blood flow control.
We report here that the level of endothelin-1 (ET-1) mRNA from bovine aortic endothelial cells grown in vitro is rapidly (within 1 h of exposure) and significantly (fivefold) decreased in response to fluid shear stress of physiological magnitude. The downregulation of ET-1 mRNA occurs in a dose-dependent manner that exhibits saturation above 15 dyn/cm2. The decrease is complete prior to detectable changes in endothelial cell shape and is maintained throughout and following alignment in the direction of blood flow. Peptide levels of ET-1 secreted into the media are also reduced in response to fluid shear stress. Cyclical stretch experiments demonstrated no changes in ET-1 mRNA, while increasing media viscosity with dextran showed that the downregulation is a specific response to shear stress and not to fluid velocity. Although both pulsatile and turbulent shear stress of equal time-average magnitude elicited the same decrease in ET-1 mRNA as steady laminar shear (15 dyn/cm2), low-frequency reversing shear stress did not result in any change. These results show that the magnitude as well as the dynamic character of fluid shear stress can modulate expression of ET-1 in vascular endothelium.
Background:
To test the hypothesis that endothelin-1 contributes to cardiac fibrosis, cardiac collagen deposition was studied in deoxycorticosterone acetate-salt (DOCA-salt) hypertensive rats, in which the endothelin system is activated. The effects of the ET(A)-selective endothelin receptor antagonist A-127722 were evaluated.
Methods and results:
A-127722 (30 mg/kg per day) was administered for 4 weeks. Myocardial fibrosis was evaluated after Sirius red F3BA staining. Systolic blood pressure was 103+/-1.6 mm Hg in unilaterally nephrectomized rats (Uni-Nx), 202+/-3.2 mm Hg in DOCA-salt rats (P:<0.01 versus Uni-Nx), and 182+/-3.1 mm Hg in ET(A) antagonist-treated DOCA-salt rats (P:<0.01 versus DOCA-salt or Uni-Nx). In DOCA-salt rats, interstitial and perivascular collagen density was increased in the subendocardial and midmyocardial regions of the left ventricle (3- to 4-fold, P:<0.05), whereas in subepicardial myocardium, the increase was predominantly perivascular. The ET(A) antagonist prevented cardiac fibrosis in DOCA-salt rats. Procollagen I and III mRNA, which were increased in hearts of DOCA-salt rats, were normalized by ET(A) antagonist treatment. TGF-beta(1) mRNA and TGF-beta(1) protein increased at 1 week in DOCA-salt rats and were lowered in ET(A) antagonist-treated rats.
Conclusions:
ET(A) receptor-mediated collagen deposition in hearts of DOCA-salt rats results from increased procollagen synthesis associated with an initial increment in expression of TGF-beta(1). These results support the hypothesis of a role for endothelin-1 in cardiac collagen deposition in mineralocorticoid hypertension, which may have pathophysiological and pharmacological implications in hypertensive heart disease.
Objective— Peroxisome proliferator–activated receptors (PPARs) may modulate in vitro the vascular production of vasoactive peptides such as endothelin-1 (ET-1). Thus, we investigated in vivo the interaction between PPARs and ET-1 in deoxycorticosterone acetate (DOCA)–salt rats that overexpress vascular ET-1.
Methods and Results— Unilaterally nephrectomized 16-week-old Sprague-Dawley rats (Uni-Nx) were divided into 4 groups (n=6 each): control group, DOCA-salt group, DOCA-salt+PPAR-γ activator (rosiglitazone, 5 mg · kg⁻¹ · d⁻¹), or DOCA-salt+PPAR-α activator (fenofibrate, 100 mg · kg⁻¹ · d⁻¹). Systolic blood pressure was significantly increased in the DOCA-salt group (240±11 vs 121±2 mm Hg in Uni-Nx, P<0.01). Progression of hypertension was partially prevented by coadministration of rosiglitazone (172±3 mm Hg vs DOCA-salt, P<0.05) but not by fenofibrate. Both PPAR activators abrogated the increase in prepro-ET-1 mRNA content in the mesenteric vasculature of DOCA-salt rats. The media-to-lumen ratio was increased in DOCA-salt rats (10.3±0.9% vs 4.9±0.5% in Uni-Nx rats, P<0.01). Rosiglitazone and fenofibrate prevented the hypertrophic remodeling observed in DOCA-salt rats without affecting vascular stiffness. Rosiglitazone but not fenofibrate prevented endothelial dysfunction in pressurized mesenteric arteries. Finally, both rosiglitazone and fenofibrate prevented the vascular increase in superoxide anion production induced in DOCA-salt animals.
Conclusions— PPAR-α and -γ activators were able to modulate endogenous production of ET-1 and had beneficial vascular effects in endothelin-dependent hypertension.
Leptin, a protein encoded by the obese gene, is produced by adipocytes and released into the bloodstream. In obese humans, serum leptin levels are increased and correlate with the individual’s body mass index and blood pressure. Elevated serum concentrations of endothelin-1 (ET-1), a potent vasoconstrictor and mitogen, were also observed in obese subjects. The pathomechanisms underlying this ET-1 increase in obesity are poorly understood. In the present study, we investigated the influence of the ob gene product leptin on the expression of ET-1 in human umbilical vein endothelial cells (HUVECs). Binding studies using 125I-radiolabeled leptin revealed high- and low-affinity leptin binding sites on HUVECs (Kd1=13.1±3.1 nmol/L and Kd2=1390±198 nmol/L, respectively), mediating a time- and dose-dependent increase of ET-1 mRNA expression and protein secretion after incubation of HUVECs with leptin. This leptin-induced ET-1 expression was inhibited by preincubation of HUVECs with 0.75 μmol/L antisense phosphorothioate oligonucleotides directed against the leptin receptor Ob-Rb. Furthermore, after incubation with leptin, increased nuclear staining of c-fos and c-jun, the major components of the transcription factor AP-1, and increased AP-1 DNA binding were observed. Transient transfection studies with ET-1 promoter constructs showed that leptin-induced promoter activity was abolished in the absence of AP-1 binding sites or by cotransfection with a plasmid overexpressing a mutated jun, which is able to bind c-fos but not DNA. Thus, leptin upregulates ET-1 production in HUVECs via a mechanism potentially involving jun binding members of the bZIP family.
Background— Recently, reactive oxygen species (ROS) have emerged as important molecules in cardiac hypertrophy. However, the ROS-dependent signal transduction mechanism remains to be elucidated. In this study, we examined the role of an ROS-sensitive transcriptional factor, NF-κB, and a mitogen-activated protein kinase kinase kinase, apoptosis signal-regulating kinase 1 (ASK1), in G-protein–coupled receptor (GPCR) agonist (angiotensin II, endothelin-1, phenylephrine)-induced cardiac hypertrophy in isolated rat neonatal cardiomyocytes.
Methods and Results— Using an ROS-sensitive fluorescent dye, we observed an increase in fluorescence signal on addition of the GPCR agonists. The GPCR agonists induced NF-κB activation. Antioxidants such as N-acetyl cysteine, N-mercaptopropionyl glycine, and vitamin E attenuated the NF-κB activation. Infection of cardiomyocytes with an adenovirus expressing a degradation-resistant mutant of IκBα led to suppression of the hypertrophic responses. The GPCR agonists rapidly and transiently activated ASK1 in a dose-dependent manner. Infection of an adenovirus expressing a dominant-negative ASK1 attenuated the GPCR agonist–induced NF-κB activation and cardiac hypertrophy. Overexpression of a constitutively active mutant of ASK1 led to NF-κB activation and cardiac hypertrophy. Activated ASK1-induced hypertrophy was abolished by inhibition of NF-κB activation.
Conclusions— These data indicate that GPCR agonist–induced cardiac hypertrophy is mediated through NF-κB activation via the generation of ROS. ASK1 is involved in GPCR agonist–induced NF-κB activation and resulting hypertrophy.
Background— Hypertensive patients have both impaired endothelium-dependent vasodilation and increased activity of the endothelin (ET-1) system, which participate in their increased vascular tone and may predispose them to atherosclerosis. This study investigated the contribution of increased ET-1 activity to the impaired endothelium-dependent vasodilator function of hypertensive patients.
Methods and Results— Forearm blood flow (FBF) responses to intraarterial infusion of acetylcholine (ACh; 7.5, 15, and 30 μg/min) and sodium nitroprusside (SNP; 0.8,1.6, and 3.2 μg/min) were assessed by strain-gauge plethysmography before and after nonselective blockade of ETA and ETB receptors by combined infusion of BQ-123 (ETA blocker; 100 nmol/min) and BQ-788 (ETB blocker; 50 nmol/min). During saline administration, the vasodilator response to ACh was significantly blunted in hypertensive patients compared with controls (P<0.001), whereas the vasodilator effect of SNP was not different between groups (P=0.74). Blockade of ET-1 receptors resulted in a significant increase in FBF from baseline in hypertensive patients (P<0.008) but not in controls (P=0.15). In hypertensive patients, a combined ETA/B blockade resulted in a significant potentiation of the vasodilator response to ACh compared with saline (P=0.01), whereas the response to SNP was unchanged (P=0.44). In contrast, the response to ACh was not significantly modified by ET-1 receptor antagonism in healthy subjects (P=0.14 compared with saline).
Conclusions— These findings indicate that blockade of ET-1 receptors improves endothelium-dependent vasodilator function in hypertensive patients, thereby suggesting that an increased ET-1 activity may play a role in the pathophysiology of this abnormality.
Cardiovascular remodeling associated with hypertension is characterized by increase of cardiomyocyte volume and changes in
extracellular matrix, particularly collagen deposition. To test the hypothesis that endothelin-1 contributes to fibrosis of
the heart in some models of experimental hypertension, we studied cardiac collagen in deoxycorticosterone acetate-salt hypertensive
rats (DOCA-salt), in which the endothelin system is activated, and the effect of the ETA-selective endothelin receptor antagonist, A-127722. A-127722 (30 mg/kg per day) was administered for 4 weeks to DOCA-salt
rats. Cardiac fibrosis was evaluated after Sirius Red F3BA staining of paraffin embedded sections. Systolic blood pressure
was 103 ± 1.6 mmHg in unilaterally nephrectomized rats (UniNx), 202 ± 3.2 mmHg in DOCA-salt (p < 0.01 vs UniNx) and 182 ±
3.1 mmHg in ETA-treated DOCA-salt (p < 0.01 vs DOCA-salt or UniNx). In DOCA-salt, collagen density was significantly increased in the subendocardial
(4-fold, P < 0.01) and midmyocardial regions (3-fold, P < 0.05) but not in the subepicardial myocardium of the left ventricle. The administration of ETA-receptor antagonist to DOCA-salt normalized collagen to baseline value. Subendocardial and midmyocardial collagen density
was significantly increased in DOCA-salt hypertensive rats. Both were corrected by ETA receptor antagonism, although blood pressure was only slightly lower and cardiac hypertrophy was unaffected in treated rats.
This suggests a role for endothelin-1 in cardiac collagen deposition in mineralocorticoid hypertension, which may have pathophysiological
and pharmacological implications in hypertensive heart disease.