title: 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 homocysteine-dependent 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.
authors.affiliation: Medizinische Poliklinik--Innenstadt, Klinikum der Universität München, Munich, Germany. Norbert.Weiss@med.uni-muenchen.de
authors.forename: Norbert
authors.initials: N
authors.lastname: Weiss
authors.forename: Stanley J
authors.initials: SJ
authors.lastname: Heydrick
authors.forename: Otilia
authors.initials: O
authors.lastname: Postea
authors.forename: Christiane
authors.initials: C
authors.lastname: Keller
authors.forename: John F
authors.initials: JF
authors.lastname: Keaney
authors.forename: Joseph
authors.initials: J
authors.lastname: Loscalzo
mesh_terms: D000818:Animals; D004730:Endothelium, Vascular / Q000378:metabolism*; D006710:Homocysteine / Q000097:blood*; D006801:Humans; D020138:Hyperhomocysteinemia / Q000097:blood / Q000150:complications / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000097:blood / Q000378:metabolism*; D014652:Vascular Diseases / Q000097:blood / Q000209:etiology / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D006710:Homocysteine