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Endothelial dysfunction and atherothrombosis in mild hyperhomocysteinemia

Medical Policlinic, University Hospital - Innenstadt, Munich, Germany, nweiss{at}medpoli.med.uni-muenchen.de

Christiane Keller

Medical Policlinic, University Hospital - Innenstadt, Munich, Germany

Ulrich Hoffmann

Medical Policlinic, University Hospital - Innenstadt, Munich, Germany

Joseph Loscalzo

Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA

Mildly elevated plasma homocysteine levels are an independent risk factor for atherothrombotic vascular disease in the coronary, cerebrovascular, and peripheral arterial circulation. Endothelial dysfunction as manifested by impaired endothelium-dependent regulation of vascular tone and blood flow, by increased recruitment and adhesion of circulating inflammatory cells to the endothelium, and by a loss of endothelial cell antithrombotic function contributes to the vascular disorders linked to hyperhomocysteinemia. Increased vascular oxidant stress through imbalanced thiol redox status and inhibition of important antioxidant enzymes by homocysteine results in decreased bioavailability of the endothelium-derived signaling molecule nitric oxide via oxidative inactivation. This plays a central role in the molecular mechanisms underlying the effects of homocysteine on endothelial function. Supplementation of folic acid and vitamin B₁₂ has been demonstrated to be efficient in lowering mildly elevated plasma homocysteine levels and in reversing homocysteine-induced impairment of endothelium-dependent vasoreactivity. Results from ongoing intervention trials will determine whether homocysteine-lowering therapies contribute to the prevention and reduction of atherothrombotic vascular disease and may thereby provide support for the causal relationship between hyperhomocysteinemia and atherothrombosis.

Key Words: atherosclerosis • B vitamins • endothelial function • homocysteine • nitric oxide • oxidant stress • thrombosis

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