Several mechanisms may be involved in the genesis of vascular disease by homocysteine, including effects on connective tissue, smooth-muscle cells, platelets, endothelial cells, blood lipids, coagulation factors, and nitric oxide-summarized here. The relative importance of each of these mechanisms is not fully understood.
Homocysteine is toxic to endothelial cells in vitro, and in vivo. Hyperhomo-cysteinemia is associated with impaired endothelium-dependent vasodilation and impaired endogenous tissue-type plasminogen activator activity. Homocysteine promotes increased platelet aggregation as a consequence of increased synthesis ofthromboxane~ and decreased synthesis
of prostaglandin. Hyperhomocysteinemia is associated with abnormalities of the clotting cascade. Homocysteine promotes the binding of lipoprotein (a) to fibrin and the growth of smooth muscle cells, and tHcy levels correlate with levels of fibrinogen, an independent risk factor for CVD. It must be noted, however, that many of these effects are not specific to homocysteine; a variety of free thiol-group amino acids, particularly cysteine, show similar tendencies. Much of the research into mechanisms has been carried out at millimolar concentrations of homocysteine, which are 100 - 1000-fold higher than those observed in vivo. In addition, the complex redox reac-tions involving the various homocysteine forms and their relation to other thiols in vivo are difficult to represent accurately in vitro where a single homocysteine species is used.
The complexities of elucidating an atherogenic mechanism are illustrated by the fact that oxidative modification of LDL by tHcy has been demonstrated in vitro and in animal models, but has not been observed in hyperhomocysteinemic patients. Similarly, supplementation with B-group vitamins, postulated to reduce tHcy and thus inhibit lipid peroxidation, had no effect on the susceptibility of LDL to oxidation. Homocysteine's effect on endothelial dysfunction, however, has been confirmed in a clinical setting. The blocking of the effects of hyperhomocysteinemia on endothelial dysfunction by pretreatment with antioxidant vitamins still suggests the involvement of an oxidative mechanism.
Similarly, in a cross-sectional study, plasma tHcy was associated strongly (r = 0'.40, p < 0.001) with plasma F-2-isoprostane levels, a marker for in vivo lipid peroxidation. The observation by Glueck and associates of a higher risk of myocardial infarction in hyperlipidemic patients with hyperhomocysteinemia and low HDL also suggests the possibility of an interaction between these risk factors.
