Mechanisms of homocysteine-induced atherothrombosis.
Elevation of plasma homocysteine level is a risk factor for cardiovascular disease, stroke, and venous thromboembolism. It is still uncertain, however, whether hyperhomocysteinemia is a causative factor or a marker of vascular disease. The strongest evidence that homocysteine plays a causal role in atherothrombosis has been provided by studies using animal models. In the past decade, considerable progress in defining the vascular effects of hyperhomocysteinemia was achieved through the use of genetic and dietary approaches to induce hyperhomocysteinemia in experimental animals. A key vascular phenotype observed in hyperhomocysteinemic animals is endothelial dysfunction, manifested by decreased bioavailability of endothelium-derived nitric oxide. Impairment of endothelial function may be mediated by either accelerated oxidative inactivation of nitric oxide or inhibition of nitric oxide production caused by the endogenous nitric oxide synthase inhibitor, asymmetric dimethylarginine. Hyperhomocysteinemia also increases susceptibility to arterial thrombosis and accelerates the development of atherosclerosis in susceptible models such as the apolipoprotein E-deficient mouse. Mechanisms of atherothrombosis may include homocysteine-induced thiolation or acylation of plasma or endothelial proteins and endoplasmic reticulum stress, which activates signal transduction pathways leading to inflammation and apoptosis.
Lentz
S R
SR
Department of Internal Medicine, The University of Iowa, and Veterans Affairs Medical Center, Iowa City, IA 52242, USA. steven-lentz@uiowa.edu
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D017209:Apoptosis; D001120:Arginine / Q000031:analogs & derivatives / Q000737:chemistry; D050197:Atherosclerosis; D003328:Coronary Thrombosis / Q000097:blood* / Q000209:etiology*; D003545:Cysteine / Q000737:chemistry; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism; D006710:Homocysteine / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D020138:Hyperhomocysteinemia / Q000378:metabolism; D007249:Inflammation; D008715:Methionine / Q000737:chemistry; D051379:Mice; D008954:Models, Biological; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism; D010641:Phenotype; D015398:Signal Transduction
D001057:Apolipoproteins E; C487735:dimethylarginine; D006710:Homocysteine; D009569:Nitric Oxide; D001120:Arginine; D008715:Methionine; D003545:Cysteine; D010100:Oxygen