Influence of Hyperhomocysteinemia on the Cellular Redox State – Impact on Homocysteine-Induced Endothelial Dysfunction

Abstract

Hyperhomocysteinemia is an independent risk factor for the development of atherosclerosis. An increasing body of evidence has implicated oxidative stress as being contributory to homocysteine's deleterious effects on the vasculature. Elevated levels of homocysteine may lead to increased generation of superoxide by a biochemical mechanism involving nitric oxide synthase, and, to a lesser extent, by an increase in the chemical oxidation of homocysteine and other aminothiols in the circulation. The resultant increase in superoxide levels is further amplified by homocysteinedependent alterations in the function of cellular antioxidant enzymes such as cellular glutathione peroxidase or extracellular superoxide dismutase. One direct clinical consequence of elevated vascular superoxide levels is the inactivation of the vasorelaxant messenger nitric oxide, leading to endothelial dysfunction. Scavenging of superoxide anion by either superoxide dismutase or 4,5-dihydroxybenzene 1,3-disulfonate (Tiron) reverses endothelial dysfunction in hyperhomocysteinemic animal models and in isolated aortic rings incubated with homocysteine. Similarly, homocysteine-induced endothelial dysfunction is also reversed by increasing the concentration of the endogenous antioxidant glutathione or overexpressing cellular glutathione peroxidase in animal models of mild hyperhomocysteinemia. Taken together, these findings strongly suggest that the adverse vascular effects of homocysteine are at least partly mediated by oxidative inactivation of nitric oxide.

Extracellular superoxide dismutase (ecSOD) in vascular biology: an update on exogenous gene transfer and endogenous regulators of ecSOD

“…98,99 The resultant increase in levels may in part be counterbalanced by homocysteine-dependent increases in ecSOD. 100 For example, Wilcken et al 101 reported a positive correlation between plasma levels of homocysteine and ecSOD in patients with coronary artery disease, and therapy that lowered plasma homocysteine also decreased ecSOD levels. 101 ecSOD levels were correlated inversely with the incidence of cardiovascular disease in these patients, and risk factors for coronary artery disease, such as male gender and smoking, were associated with decreased levels of ecSOD in a previous study.…”

Mechanisms of H2O2-induced oxidative stress in endothelial cells

“…Previous studies by Landmesser et al 2002; and Loscalzo et al (Welch et al 1997;Maytin et al 1999;Forgione et al 2000;Trolliet et al 2001;Nedeljkovic et al 2003;Weiss et al 2003) demonstrate that oxidative stress is an important molecular component of vascular disease, including hypertension and atherosclerosis. Increased understanding of the enzymatic and molecular development of cardiovascular disease may allow for more effective treatment and earlier intervention.…”

Biochemical and Pharmacokinetic Properties of Aspergillus flavipes Glutathione-Homocystine Transhydrogenase of Unique Affinity for Homocystine Reduction using GSH as Hydrogen Donor

“…Oxidation of soluble homocysteine to highly insoluble homocystine is the main noticeable biochemical reason raised for various cardiovascular diseases, atherosclerosis, Alzheimer and diabetes [5,8]. GHTHase was characterized in our preliminary studies [3] from Aspergillus flavipes, exhibiting a unique catalytic and biochemical properties comparing to glutathione-s-transferase.…”

“…Elevations in plasma homo-cysteine may be due to the genetic defects in its catabolizing enzymes or nutritional deficiencies in vitamin cofactors. Recently, homocysteinuria was endorsed as the main risk factor for various cardiovascular diseases such as atherosclerosis, thrombogenicity, mal endothelial function, atherothrombosis, Alzheimer's and diabetics [4][5][6][7][8]. The toxicity of homocystine arises from its strong chemical stability, insolubility, with feasibility of accumulation in small arteries causing atherosclerosis [7,8].…”