Death receptor induced apoptosis: a new mechanism of homocysteine-mediated endothelial cell cytotoxicity.

Abstract

The hypothesis that homocysteine (Hcy) is atherogenic was proposed more than 30 years ago.1 People with inherited disorders of Hcy and methionine metabolism due to rare mutations such as in the cystathionine β-synthase gene present with a severe form of hyperhomocysteinemia that is characterized by premature atherosclerosis and thrombotic disease. A common variant in the metylenetetrahydrofolate reductase gene, 677C to T, is associated with decreased enzyme activity leading to mild hyperhomocysteinemia in humans.2 This mutation is present in the homozygous state in 10% to 15% of North American and European populations.2 Epidemiological studies in the general population have indicated a positive correlation between an elevation of total plasma Hcy and stroke, myocardial infarction, peripheral vascular disease, and venous thromboembolism.3 Whereas a significant association between Hcy levels and clinical cardiovascular events has not been observed in all prospective studies, hyperhomocysteinemia is now considered by many to be an independent risk factor for atherosclerotic vascular disease. Furthermore, the belief that hyperhomocysteinemia may be not only a marker but also a cause for atherosclerosis and thrombosis has intensified research in this area. Hcy is a thiol amino acid, but only a small fraction (<2%) circulates in the thiol form. The reminder is a mixture of disulfide derivatives, including protein-bound disulfides. Hyperhomocysteinemia is usually defined as an elevation of plasma Hcy above 15 μmol/L. This elevation may be caused by genetic defects, renal insufficiency, certain drugs, or nutritional insufficiencies of cofactors required for Hcy metabolism, including folate, vitamin B2 (riboflavin), vitamin B6 (pyridoxal phosphate), or vitamin B12 (methylcobalamin). Because plasma Hcy can be lowered by oral supplementation of folic acid or …