Hyperhomocyst(e)inemia Is a Risk Factor for Arterial Endothelial Dysfunction in Humans

Woo, Kam S.; Chook, Ping; Lolin, Y. I.; Cheung, Alice Siu Ping; Chan, Loi Yuen; Sun, Yang; Sanderson, John E.; Metreweli, C.; Celermajer, D.

doi:10.1161/01.cir.96.8.2542

Cited by 410 publications

(137 citation statements)

References 25 publications

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“…Collagen-induced vasoconstriction also increased, probably through a decrease in the vasodilator responsiveness to platelet-generated ADP (Lentz, 1997;Lentz et al, 1996). This alteration of the endothelium-mediated vasorelaxation is also observed in healthy subjects affected with moderate hyperhomocysteinemia (Tawakol et al, 1997;Woo et al, 1997). The crossover study of an oral methionine load by Bellamy et al (1998) dependent vasodilation.…”

Section: Alterations Of Vascular Thromboresistancementioning

confidence: 83%

Impaired Homocysteine Metabolism and Atherothrombotic Disease

Durand

Prost²,

Loreau

et al. 2001

Laboratory Investigation

224

147

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SUMMARY:Based on recent retrospective, prospective, and experimental studies, mild to moderate elevation of fasting or postmethionine-load plasma homocysteine is accepted as an independent risk factor for cardiovascular disease and thrombosis in both men and women. Hyperhomocysteinemia results from an inhibition of the remethylation pathway or from an inhibition or a saturation of the transsulfuration pathway of homocysteine metabolism. The involvement of a high dietary intake of methionine-rich animal proteins has not yet been investigated and cannot be ruled out. However, folate deficiency, either associated or not associated with the thermolabile mutation of the N 5,10 -methylenetetrahydrofolate reductase, and vitamin B 6 deficiency, perhaps associated with cystathionine ␤-synthase defects or with methionine excess, are believed to be major determinants of the increased risk of cardiovascular disease related to hyperhomocysteinemia. Recent experimental studies have suggested that moderately elevated homocysteine levels are a causal risk factor for atherothrombotic disease because they affect both the vascular wall structure and the blood coagulation system. The oxidant stress that results from impaired homocysteine metabolism, which modifies the intracellular redox status, might play a central role in the molecular mechanisms underlying moderate hyperhomocysteinemia-mediated vascular disorders. Because folate supplementation can efficiently reduce plasma homocysteine levels, both in the fasting state and after methionine loading, results from further prospective cohort studies and from on-going interventional trials will determine whether homocysteine-lowering therapies can contribute to the prevention and reduction of cardiovascular risk. Additionally, these studies will provide unequivocal arguments for the independent and causal relationship between hyperhomocysteinemia and atherothrombotic disease. (Lab Invest 2001, 81:645-672).C ardiovascular diseases remain the leading cause of mortality in Western populations. Hyperlipoproteinemia, hypertension, diabetes, obesity, and tobacco smoking are the main risk factors for atherosclerosis and its thrombotic complications. However, these factors alone cannot account for all of the deaths caused by vascular pathologies.As early as 1969, clinical studies conducted in homocystinuric children revealed the importance of severe hyperhomocysteinemia in premature development of atherosclerosis and thromboembolism (McCully, 1983). According to numerous retrospective case-controlled studies, moderate increases in plasma homocysteine, which can be precisely quantitated by high performance liquid chromatography (HPLC), raise the risk for cardiovascular disease 2-fold, after adjusting for classic risk factors. Moreover, up to 20% to 40% of patients with vascular pathologies present moderate to intermediate hyperhomocysteinemia. However, results from prospective studies are inconsistent. Additionally, molecular mechanisms underlying hyperhomocysteinemia-induced vascular diseas...

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Section: Alterations Of Vascular Thromboresistancementioning

confidence: 83%

Impaired Homocysteine Metabolism and Atherothrombotic Disease

Durand

Prost²,

Loreau

et al. 2001

Laboratory Investigation

224

147

View full text Add to dashboard Cite

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“…However, as discussed above, capillary transit time is calculated to be Ϸ1 sec, minimizing its effect on the time difference between the peaks of f low velocity and plasma NO concentration. With increasing coronary blood f low, the blood volume in the coronary microvessels could be increased (55). This result may cause the decrease in NO concentration, obscuring the increase in NO production in the coronary circulation.…”

Section: Resultsmentioning

confidence: 99%

Evaluation of bioavailability of nitric oxide in coronary circulation by direct measurement of plasma nitric oxide concentration

Neishi

Mochizuki²,

Miyasaka³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Although bioavailability of NO in the coronary circulation is commonly evaluated by acetylcholine (ACh)-induced vasodilation, a change in plasma NO concentration and its relation to the flow response after injection of ACh are still unknown. Thus, we directly measured the concentration of NO in the coronary sinus by using a catheter-type NO sensor for coronary sinus. An NO-sensitive sensor was located and fixed in a 4-Fr catheter with a soft tip for protection of vascular wall. After calibration with an NO-saturated pure water, the catheter-type NO sensor was located in the coronary sinus in anesthetized dogs. The coronary flow velocity (CFV) was measured with a Doppler guide wire. Intracoronary injection of ACh (0.4 and 1.0 g͞kg) increased plasma NO concentration in a dose-dependent manner (3-10 nM). Although ACh increased CFV by 95%, there was no significant difference between the two ACh doses. After ACh, the peak value of plasma NO concentration was observed significantly later than CFV. N G -methyl-L-arginine (NO synthase inhibitor) decreased basal NO concentration by 3 nM and suppressed the ACh-induced NO synthesis with no significant change in average peak velocity. We conclude that production of NO in the coronary circulation can be evaluated in the coronary sinus. Although ACh increases both CFV and NO concentration, CFV dose not reflect NO concentration in terms of magnitude and time course. Direct measurement of plasma NO concentration by the catheter-type NO sensor is useful to evaluate bioavailability of NO in the coronary circulation.nitric oxide synthase ͉ nitric oxide-selective sensor ͉ acetylcholine ͉ coronary blood flow ͉ endothelial function N itric oxide (NO) released by endothelial cells is formed from L-arginine by nitric oxide synthase (NOS) (1). NO release is augmented by mechanical stimulation such as shear stress (2-6), pulsatile flow (7, 8), and axial strain (9). Such mechanical stresses, which are produced by the periodic myocardial contraction and relaxation, directly influence the coronary blood vessels, acting as an overwhelmingly dominant factor of the coronary blood flow regulation (10-12). Under the stimulatory influences by the mechanical stresses, coronary endothelial cells produce NO on a beat-to-beat basis (13). In the coronary circulation, endothelium-derived NO plays fundamental roles in the regulation of blood flow, exerting a tonic vasodilator influence at rest and with increasing myocardial metabolism (14).However, bioavailability of NO is diminished in the subjects with a wide range of cardiac risk factors and pathologic conditions, such as aging, gender, smoking, hypertension, hypercholesterolemia, diabetes mellitus, hyperhomocystinemia, heart failure, infections, and polymorphisms of the endothelial NOS (15-23). Importantly, endothelial dysfunction, characterized by decreased bioavailability of NO, is a predictor of cardiovascular risk and outcome (24-28).Several techniques have been used to evaluate the endothelial function or bioavailability of NO (29). Coronary en...

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“…Animal models of mild hyperhomocyst(e)inemia manifest impaired endothelium-dependent vasoreactivity and regulation of blood flow, whether induced by vitamin deficiency (6), disruption of the cystathionine ␤-synthase (CBS) gene (7), or both (8). Impaired endothelium-dependent vasodilator function, but preserved endothelium-independent vasodilator response, is also a common finding in humans with either acutely elevated plasma tHcy levels after a methionine challenge (9)(10)(11)(12) or with chronic, mild hyperhomocyst(e)inemia (13,14). In accordance with these in vivo findings, homocysteine (HcyH) has been shown to decrease the production and͞or bioactivity of NO and Snitrosothiols by cultured endothelial cells (15,16).…”

mentioning

confidence: 99%

Overexpression of cellular glutathione peroxidase rescues homocyst(e)ine-induced endothelial dysfunction

Weiss

Heydrick

Bierl

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

196

140

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Homocyst(e)ine (Hcy) inhibits the expression of the antioxidant enzyme cellular glutathione peroxidase (GPx-1) in vitro and in vivo, which can lead to an increase in reactive oxygen species that inactivate NO and promote endothelial dysfunction. In this study, we tested the hypothesis that overexpression of GPx-1 can restore the normal endothelial phenotype in hyperhomocyst(e)inemic states. Heterozygous cystathionine ␤-synthase-deficient (CBS (؊/؉) ) mice and their wild-type littermates (CBS (؉/؉) ) were crossbred with mice that overexpress GPx-1 [GPx-1 (tg؉) mice]. GPx-1 activity was 28% lower in CBS (؊/؉) ͞GPx-1 (tg؊) compared with CBS (؉/؉) ͞GPx-1 (tg؊) mice (P < 0.05), and CBS (؊/؉) and CBS (؉/؉) mice overexpressing GPx-1 had 1.5-fold higher GPx-1 activity compared with GPx-1 nontransgenic mice (P < 0.05). Mesenteric arterioles of CBS (؊/؉) ͞ GPx-1 (tg؊) mice showed vasoconstriction to superfusion with ␤-methacholine and bradykinin (P < 0.001 vs. all other groups), whereas nonhyperhomocyst(e)inemic mice [CBS (؉/؉) ͞GPx-1 (tg؊) and CBS (؉/؉) ͞GPx-1 Mild hyperhomocyst(e)inemia is a risk factor for atherothrombotic vascular disease (reviewed in refs. 1-5). Endothelial dysfunction appears to play a key role in homocyst(e)ine (Hcy)-mediated vascular pathophysiology. Animal models of mild hyperhomocyst(e)inemia manifest impaired endothelium-dependent vasoreactivity and regulation of blood flow, whether induced by vitamin deficiency (6), disruption of the cystathionine ␤-synthase (CBS) gene (7), or both (8). Impaired endothelium-dependent vasodilator function, but preserved endothelium-independent vasodilator response, is also a common finding in humans with either acutely elevated plasma tHcy levels after a methionine challenge (9-12) or with chronic, mild hyperhomocyst(e)inemia (13,14). In accordance with these in vivo findings, homocysteine (HcyH) has been shown to decrease the production and͞or bioactivity of NO and Snitrosothiols by cultured endothelial cells (15,16).One mechanism proposed to explain the adverse effects of Hcy on endothelial function involves oxidant stress with resulting depletion of bioavailable NO (17). HcyH undergoes autooxidation when added to plasma, leading to the formation of reactive oxygen species, including hydrogen peroxide and superoxide anion (18). Superoxide anion can react with NO to form peroxynitrite, which leads to inactivation of its biological function (19). Hydrogen peroxide decomposes to the toxic oxygen species hydroxyl radical, which is highly reactive and causes lipid peroxidation. Elevated levels of lipid peroxides lead to an increase in peroxyl radicals that can, as well, inactivate NO through the formation of lipid peroxynitrites. Homocysteineinduced vascular oxidant stress may be additionally aggravated by an Hcy-mediated, specific decrease in the expression of the cellular isoform of glutathione peroxidase (GPx-1), as recently shown in vitro and in vivo (15, 20, §). This key enzyme for the cellular defense against oxidant stress uses glutathione to reduce hydro...

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Hyperhomocyst(e)inemia Is a Risk Factor for Arterial Endothelial Dysfunction in Humans

Abstract: Hyperhomocysteinemia is an independent risk factor for arterial endothelial dysfunction in healthy middle-aged adults.

Cited by 410 publications

References 25 publications

Impaired Homocysteine Metabolism and Atherothrombotic Disease

Impaired Homocysteine Metabolism and Atherothrombotic Disease

Evaluation of bioavailability of nitric oxide in coronary circulation by direct measurement of plasma nitric oxide concentration

Overexpression of cellular glutathione peroxidase rescues homocyst(e)ine-induced endothelial dysfunction

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