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In the present study we tested the hypothesis whether hyperhomocysteinemia, an elevated homocysteine level, induces venous phenotype in artery. To test our hypothesis, we employed wild type (WT) and cystathionine β-synthase heterozygous (+/-) (CBS+/-) mice treatment with or without folic acid (FA). Aortic blood flow and velocity were significantly...
Citations
... SAH is a strong product inhibitor of SAM-dependent methyltransferases and its accumulation can interfere with numerous cellular processes (6). In particular, SAH accumulation is associated with altered collagen/elastin expression (70), inhibition of expression of the collagen crosslinking enzyme lysyl oxidase (71), decreased elastin/collagen ratio (70,72), mitochondrial dysfunction (73) and deregulated lipid metabolism (19,53,74). Also deregulated DNA methylation is linked to HHcy. ...
Atherosclerosis, the leading cause of cardiovascular disease, cannot be sufficiently explained by established risk factors such as cholesterol. Elevated plasma homocysteine (Hcy) is an independent risk factor for atherosclerosis and is closely linked to cardiovascular mortality. However, its role in atherosclerosis has not been fully clarified. We have previously shown that rabbits fed a diet deficient in B vitamins and choline (VCDD), required for Hcy degradation, exhibit an accumulation of macrophages and lipids in the aorta, impairment of its biomechanical properties, and disorganization of aortic collagen in the absence of hypercholesterolemia and an aggravation of atherosclerosis in its presence. In the current study, plasma Hcy levels were increased by intravenous injections of Hcy into balloon-injured rabbits fed VCDD in the absence of hypercholesterolemia. This led to VCDD-like thin collagen-containing plaques with low levels of macrophages and lipids, massive accumulation of VLDL-triglycerides as well as an impaired K ⁺ -induced contraction and acetylcholine-induced relaxation of the aorta compared to rabbits fed VCDD alone. The observed elastin fragmentation and collagen disorganization indicate remodeling of scaffold proteins in response to elevated Hcy. Decreased total protein methylated arginine in blood cells and liver as well as altered metabolic profiles in blood cells, serum, and liver suggest additional mechanisms triggered in response to elevated plasma Hcy levels. We therefore conclude that elevated Hcy contributes to atherogenic transformation of the aorta not only in the presence but also in the absence of hypercholesterolemia.
... Because HHcy may be associated with pathologic conditions, the reduction of Hcy levels becomes important. Indeed, chronic hyperhomocysteinemia causes vascular remodeling by instigating vein phenotype in artery thus leading to cerebrovascular and vascular dysfunctions [25,26]. The risk of mortality increases for each 5-µmol/L Hcy by 33.6% [27]. ...
Hyperhomocysteinemia is recognized as risk factor for cardiovascular and age-associated diseases. Folic acid supplementation efficiently lowers plasma homocysteine (Hcy) levels, but high intake may negatively affect health because of unnatural levels of unmetabolized folic acid in the systemic circulation. Oxoproline (Oxo) provides by glutamic acid production an increase of intracellular folic acid trapping. Aim of this study was to compare the efficacy of three supplementation protocols: (1) traditional therapy (5-methyl-tetrahydrofolate: 15 mg/day); (2) 5 mL/day of Oxo with 300 μg folic acid (oxifolic); (3) 5 mL/day of Oxo alone (magnesio+) in a 90 days randomized trial on thirty-two moderate hyperhomocysteinemic (18.6 ± 2.4 μmol.L−1) patients (age 48 ± 14 yrs). Thiols: cysteine (Cys), cysteinylglycine (Cys–Gly) and glutathione levels were assessed too. Every supplementation induced significant (p range <0.05–0.0001) reductions of Hcy level and Cys concentration after the three protocols adopted. Otherwise glutathione concentration significantly increased after oxifolic (p < 0.01) and traditional (p < 0.05) supplementation. The integration of Oxo resulted an interesting alternative to traditional therapy because absence or minimal number of folates in the integrator eliminates any chance of excess that can constitute a long-term risk.
... These data indicate that under physiological conditions, H2S production from CBS is not maximal and can be further enhanced by allosteric activation of the enzyme. The conclusion that CBS-derived H2S plays a physiological role in maintaining (i.e., physiologically lowering blood pressure) is indirectly supported by the above data, as well as by the findings demonstrating that CBS-deficient mice exhibit elevated blood pressure [126,127,142], by data showing that pharmacological inhibition of CBS-alone (and especially in combination with inhibition of CSE)-can elevate blood pressure in rats [143,144] . Moreover, according to a meta-analysis, the c.833T>C(p.Ile278Thr) polymorphism (a 68 bp insertion at 844 in the exon 8, which produces a form of CBS that has lower specific activity and produces mild hyperhomocysteinemia) is associated with a significantly higher risk of stroke [145]. ...
Cystathionine-β-synthase (CBS), the first (and rate-limiting) enzyme in the transsulfuration pathway, is an important mammalian enzyme in health and disease. Its biochemical functions under physiological conditions include the metabolism of homocysteine (a cytotoxic molecule and cardiovascular risk factor) and the generation of hydrogen sulfide (H2S), a gaseous biological mediator with multiple regulatory roles in the vascular, nervous, and immune system. CBS is up-regulated in several diseases, including Down syndrome and many forms of cancer; in these conditions, the preclinical data indicate that inhibition or inactivation of CBS exerts beneficial effects. This article overviews the current information on the expression, tissue distribution, physiological roles, and biochemistry of CBS, followed by a comprehensive overview of direct and indirect approaches to inhibit the enzyme. Among the small-molecule CBS inhibitors, the review highlights the specificity and selectivity problems related to many of the commonly used “CBS inhibitors” (e.g., aminooxyacetic acid) and provides a comprehensive review of their pharmacological actions under physiological conditions and in various disease models.
... The prevalence of hyperhomocysteinemia is significantly higher in patients with hypertension and ischemic heart disease (Asfar and Safar, 2007). Chronic hyperhomocysteinemia causes vascular remodeling by instigating vein phenotype in artery thus leading to cerebrovascular and vascular dysfunctions (Basu et al., 2011). ...
There are numerous theories of aging, a process which still seems inevitable. Aging leads to cancer and multi-systemic disorders as well as chronic diseases. Decline in age- associated cellular functions leads to neurodegeneration and cognitive decline that affect the quality of life. Accumulation of damage, mutations, metabolic changes, failure in cellular energy production and clearance of altered proteins over the lifetime, and hyperhomocysteinemia, ultimately result in tissue degeneration. The decline in renal functions, nutritional deficiencies, deregulation of methionine cycle and deficiencies of homocysteine remethylation and transsulfuration cofactors cause elevation of homocysteine with advancing age. Abnormal accumulation of homocysteine is a risk factor of cardiovascular, neurodegenerative and chronic kidney disease. Moreover, approximately 50% of people, aged 65 years and older develop hypertension and are at a high risk of developing cardiovascular insufficiency and incurable neurodegenerative disorders. Increasing evidence suggests inverse relation between cognitive impairment, cerebrovascular and cardiovascular events and renal function. Oxidative stress, inactivation of nitric oxide synthase pathway and mitochondria dysfunction associated with impaired homocysteine metabolism lead to aging tissue degeneration. In this review, we examine impact of high homocysteine levels on changes observed with aging that contribute to development and progression of age associated diseases.
... This finding indicates that in HHcy mice, it is more likely there is greater collagen deposition and aortic stiffening than among other groups, causing reduced blood flow. Similar results have been shown previously in our laboratory [28]. HHcy is an independent risk factor for arterial endothelial dysfunction as shown by Woo et al. [29] Their results suggest that Hcy levels are the strongest predictor for impaired endothelium-dependent flow-mediated dilation, independent of age, sex, BMI, or BP, folate, vitamin B12 and cholesterol levels. ...
Objective:
The objective of this study was to define the mechanisms of homocysteine-induced effects on the aortic wall that promote vascular remodeling and hypertension as well as explore the role of Toll-like receptor 4 in homocysteine-induced effects.
Method:
Five strains of mice were utilized in this study: C57BL/6J, C3H/HeOuJ, CBS+/-, C3H/HeJ and CBS+/-/C3H. Aorta, heart and blood were collected at the end of the experiments. Blood pressure (BP) was recorded using noninvasive tail cuff method. To determinate effects of vasoactive agent and endothelial-dependent vasodilator on aorta contractility, we performed vascular function measurements. In addition, the expression of mitochondrial fusion and fission proteins, antioxidant markers and collagen fragments were assessed.
Results:
BP measurements demonstrated a significant increase in SBP and DBPs in CBS+/- mice compared with other groups. CBS+/- mice aorta had lower response to phenylephrine and acetylcholine compared with other groups; however, CBS+/-/C3H mice response was improved. Dynamin-related protein 1 protein expression was significantly upregulated in CBS+/- mice, whereas C3H mice showed downregulation. In addition, CBS+/- mice showed increased oxidative stress, inflammation and decreased nitric oxide. These effects were normalized in CBS+/-/C3H mice.
Conclusion:
Our findings demonstrate the dominance of endothelial cell mitochondrial fission over mitochondrial fusion in hyperhomocysteinemia and oxidative stress. This may explain the endothelial cell loss and dysfunction that follows collagen deposition, which contributes to inward aorta remodeling in hypertension.
... Vacek et al (29) used a mouse experimental model and found that a mechanical injury of the carotid artery led to an increase in the TIMP-3 level in the injured artery. Similar results were obtained by Basu et al (30). In mice with chronic hyperhomocysteinemia, an increase in TIMP-3 gene expression was observed in the aorta. ...
Tissue inhibitors of metalloproteinases (TIMPs) control the activity of metalloproteinases. Elastin‑derived peptides (EDPs) are generated as a result of the degradation of elastin fibers. The EDPs bind to the elastin receptor and exert numerous biological effects. The aim of the present study was to compare the production of TIMP‑1, TIMP‑2 and TIMP‑3 and their ratios in human endothelial cells (ECs) derived from three clinically important vascular localizations (coronary arteries, aorta and iliac artery), and evaluate the influence of a well‑known EDP, κ‑elastin. The highest concentration of TIMP‑1 was identified in the aortic ECs, while the lowest concentration was observed in the ECs derived from the coro‑ nary artery. The opposite pattern was observed for TIMP‑2 production. When the TIMP‑3 concentration was analyzed in the three EC lines, no statistically significant differ‑ ences were observed. Application of κ‑elastin was found to decrease the TIMP‑1 concentration in the aortic ECs, while an increase in the TIMP‑1 concentration was observed in the ECs derived from the iliac artery. The most significant decrease in TIMP‑2 concentration following κ‑elastin admin‑ istration was observed in the ECs obtained from the coronary arteries. Furthermore, the highest concentration of κ‑elastin resulted in an increase in TIMP‑3 production in the ECs derived from the coronary arteries. The following ratios of the TIMP concentrations were calculated: TIMP‑1/TIMP‑2, TIMP‑1/TIMP‑3 and TIMP‑2/TIMP‑3. Each ratio presented different values for the ECs obtained from the various local‑ izations. In the majority of cases, the addition of κ‑elastin did not significantly change these proportions. Therefore, these indicators may be characteristic features that can be used to describe ECs in various clinically important vascular localizations.
... The cardiovascular effects of homocysteine remain unclear. Hyperhomocysteinemia has been implicated in vascular damage in CBS-deficient mice that developed vascular remodeling, cardiomyocyte dysfunction, and increased apoptosis 33,34 . Similarly, mice that were fed high-fat, high-Met diets developed early and accelerated atherosclerosis 35 . ...
Dietary methionine restriction (MR) in rodents increased lifespan despite higher heart-to-body weight ratio (w/w) and hyperhomocysteinemia, which are symptoms associated with increased risk for cardiovascular disease. We investigated this paradoxical effect of MR on cardiac function using young, old, and apolipoprotein E-deficient (ApoE-KO) mice. Indeed, MR animals exhibited higher heart-to-body weight ratio (w/w) and hyperhomocysteinemia with a molecular pattern consistent with cardiac stress while maintaining the integrity of cardiac structure. Baseline cardiac function, which was measured by non-invasive electrocardiography (ECG), showed that young MR mice had prolonged QRS intervals compared with control-fed (CF) mice, whereas old and ApoE-KO mice showed similar results for both groups. Following β-adrenergic challenge, responses of MR mice were either similar or attenuated compared with CF mice. Cardiac contractility, which was measured by isolated heart retrograde perfusion, was similar in both groups of old mice. Finally, the MR diet induced secretion of cardioprotective hormones, adiponectin and fibroblast growth factor 21 (FGF21), in MR mice with concomitant alterations in cardiac metabolic molecular signatures. Our findings demonstrate that MR diet does not alter cardiac function in mice despite the presence of hyperhomocysteinemia because of the adaptive responses of increased adiponectin and FGF21 levels.
Hyperhomocysteinemia (Hhcy) was defined as an independent risk factor for cardiovascular events. A number of clinical trials had investigated the relationship between Hhcy lowering treatment and cardiovascular diseases, however, the results of these studies remain controversial. This review article gave an over view of the homocysteine metabolisms and updated the recently published results in the role of Hhcy lowering therapy on cardiovascular events. © 2012 Blackwell Publishing Ltd.
