Mechanisms of increased vascular oxidant stress in hyperhomocys-teinemia and its impact on endothelial function.
Elevated plasma levels of homocysteine are associated with an increased generation of reactive oxygen species in aortas of hyperhomocysteinemic animals and in endothelial cells. This may contribute to endothelial dysfunction observed in hyperhomocysteinemia, and promote atherosclerotic vascular disease. Homocysteine seems to promote the formation of reactive oxygen species primarily by a biochemical mechanism involving endothelial nitric oxide synthase, as increased endothelial lipid peroxidation and oxidation of the redox-sensitve dye 2',7'-dichlorofluoresceine could only be observed after incubation of endothelial cells with L-, but not with D-homocysteine, and could be prevented by inhibition of endothelial nitric oxide synthase. An increased oxidation rate of aminothiols in plasma, as observed in patients with hyperhomocysteinemia, further contributes to increased generation of reactive oxygen species. These effects are amplified by a homocysteine-specific inhibition of cellular antioxidant enzymes, like superoxide dismutase and the cellular isoform of gluthatione peroxidase. All mechanisms together result in increased levels of superoxide anion and peroxyl radicals in the vasculature that react with nitric oxide to form peroxnitrites. This abolishes nitric oxide's bioactivity and contributes to endothelial dysfunction. In addition, increased vascular oxidant stress in hyperhomocysteinemia has been shown to activate proinflammatory signaling pathways in endothelial cells, like the transcription factor NF-kappaB. This leads to increased endothelial expression of chemokines and adhesion molecules that promote the recruitment, adhesion and transmigration of circulating leukocytes to the vessel wall. All these mechamisms may contribute to the increased risk for cardiovascular diseases associated with hyperhomocysteinemia.
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Medizinische Poliklinik-Innenstadt, Klinikum der Universität München, Pettenkoferstrasse 8a, D-80336 München, Germany. Norbert.Weiss@med.uni-muenchen.de
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001808:Blood Vessels / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000502:physiology*; D006710:Homocysteine / Q000378:metabolism; D006801:Humans; D020138:Hyperhomocysteinemia / Q000097:blood / Q000150:complications / Q000378:metabolism*; D015227:Lipid Peroxidation; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000502:physiology; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
D000975:Antioxidants; D017382:Reactive Oxygen Species; D006710:Homocysteine; D013481:Superoxides; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase