Influence of hyperhomocysteinemia on the cellular redox state - Impact on homocysteine-induced endothelial dysfunction

Hyperhomocysteinemia is an independent risk factor for the
development of atherosclerosis. An increasing body of evidence has
implicated oxidative stress as being contributory to homocysteines
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,
homocysteineinduced 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.