Mechanisms of the atherogenic effects of elevated homocysteine in experimental models.
Hyperhomocysteinemia is a risk factor for cardiovascular disease and stroke. During the last decade, considerable progress in delineating the mechanisms that underlie the atherogenic effects of hyperhomocysteinemia has been achieved through the use of experimental animal models. Among the most informative animal models are those that use genetic and dietary approaches to produce hyperhomocysteinemia in mice. Recent findings demonstrate that hyperhomocysteinemia can accelerate the development of atherosclerosis in susceptible models such as the apolipoprotein E-deficient mouse. Hyperhomocysteinemia also is a potent inducer of endothelial dysfunction, particularly in small vessels such as cerebral arterioles. Mechanisms of endothelial dysfunction may include inhibition of endothelial nitric oxide synthase by its endogenous inhibitor, asymmetric dimethylarginine, and oxidative inactivation of nitric oxide mediated by upregulation of prooxidant enzymes and downregulation of antioxidant enzymes. There also is good evidence from animal models that hyperhomocysteinemia produces endoplasmic reticulum stress, which may contribute to atherosclerosis and endothelial dysfunction by activating signal transduction pathways leading to inflammation, oxidative stress, and apoptosis.
Wilson
Katina M
KM
Department of Internal Medicine, The University of Iowa, Iowa City, Iowa 52242, USA.
Lentz
Steven R
SR
D000818:Animals; D001161:Arteriosclerosis / Q000097:blood / Q000209:etiology* / Q000503:physiopathology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism / Q000503:physiopathology; D006710:Homocysteine / Q000097:blood*; D020138:Hyperhomocysteinemia / Q000097:blood / Q000139:chemically induced / Q000150:complications*; D008715:Methionine / Q000633:toxicity; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress; D012307:Risk Factors
D006710:Homocysteine; D009569:Nitric Oxide; D008715:Methionine