Homocysteine and glutathione peroxidase-1.
Mildly elevated homocysteine levels (Hcy) increase the risk for atherothrombotic vascular disease in the coronary, cerebrovascular, and peripheral arterial circulations. The molecular mechanisms responsible for decreased bioavailability of endothelium-derived nitric oxide (NO) by Hcy involve an increase of vascular oxidant stress and inhibition of important antioxidant capacity. Glutathione peroxidase-1 (GPx-1), a selenocysteine-containing antioxidant enzyme, may be a key target of Hcy's deleterious actions, and several experimental and clinical studies have demonstrated a complex relationship between plasma total homocysteine (tHcy), GPx-1, and endothelial dysfunction. Hcy may promote endothelial dysfunction, in part by decreasing GPx-1 expression; however, there is evidence to suggest that overexpression of GPx-1 can compensate for these effects. This review summarizes the current knowledge of the metabolism of Hcy, the effects of hyperhomocysteinemia observed in in vitro and in vivo models that lead to endothelial dysfunction and the possible mechanisms for these actions, and the role of GPx-1 in the pathogenesis of Hcy-induced cardiovascular disease (CVD).
Lubos
Edith
E
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Loscalzo
Joseph
J
Handy
Diane E
DE
D000818:Animals; D050197:Atherosclerosis / Q000097:blood / Q000453:epidemiology; D001682:Biological Availability; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D019317:Evidence-Based Medicine; D005979:Glutathione Peroxidase / Q000097:blood / Q000378:metabolism*; D006710:Homocysteine / Q000097:blood / Q000378:metabolism*; D006801:Humans; D020138:Hyperhomocysteinemia / Q000097:blood / Q000453:epidemiology; D008954:Models, Biological; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism / Q000493:pharmacokinetics; D013927:Thrombosis / Q000097:blood / Q000453:epidemiology