Contributions of hyperhomocysteinemia to atherosclerosis: Causal relationship and potential mechanisms

Hyperhomocysteinemia. (HHcy) is considered an independent risk factor for cardiovascular disease, including ischemic heart disease, stroke, and. peripheral vascular disease. Mutations in the, enzyme's and/or nutritional deficiencies in B vitamins required for homocysteine metabolism can induce HHcy. Studies. using genetic- or diet-induced animal models of HHcy have demonstrated a causal relationship between HHcy and accelerated atherosclerosis. Oxidative stress and activation of proinflammatory factors have been proposed to explain the atherogenic effects of HHcy. Recently, HHcy-induced endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) have. been found to play a role in. HHcy-induced atherogenesis. This review will focus on the cellular mechanisms of HHcy in atherosclerosis from both in vivo and in vitro studies. The contributions of ER stress and the UPR in atherogenesis will be emphasized. Results from recent, clinical trials assessing the cardiovascular risk of lowering total plasma homocysteine levels and new findings examining the atherogenic role of HHcy in wild-type C57BL/6J mice will also be. discussed. (C) 2009 International Union of Biochemistry and Molecular Biology, Inc. Volume 35, Number 2, March/April 2009, Pages 120-129 . E-mail: raustin@stjosham.on.ca.