PUTATIVE MECHANISMS FOR VASCULAR DAMAGE BY HOMOCYSTEINE

In homocystinuria homocysteine appears to be directly toxic to the vas culature, but in mild hyperhomocysteinaemia a cause and effect relatio nship remains unproven. Evidence for a causal role is derived from rec ent primate and human studies in which endothelial dysfunction was pro duced by modestly elevated blood homocysteine concentrations. Endothel ial dysfunction would account for an increased risk of both arterial a nd venous disease. A key abnormality may be impaired release and/or ac tion of nitric oxide in response to flow. Other possible mechanisms in clude smooth muscle cell proliferation, extracellular matrix modificat ion and lipoprotein oxidation. Although demonstrated in vitro, a role for lipoprotein oxidation in man has not been substantiated. However a n effect of homocysteine on cellular redox status remains a possible m echanism. Homocysteine does not appear to alter circulating coagulatio n factors consistently, but may promote enhanced thrombin production i ndirectly by its effects on endothelium. Further studies are required to elucidate the pathological actions of homocysteine, concentrating o n the effects of mild hyper-homocysteinaemia on endothelial function i n man.