In parallel with epidemiological studies, a significant amount of basic research has focused on the mecha-nism(s) by which homocysteine may induce atherosclerosis and thrombosis. A definitive answer has proven elusive. Potential mechanisms with significant experimental support include, but are not limited to, the following: (1) modification of the endothelial cell surface; (2) modification of plasma proteins by formation of disulfides; (3) activation of platelets; (4) modification of monocyte functions; (5) increased expression or activity of vascular adhesion molecules; and (6) oxidative damage induced by peroxides formed during disulfide bond formation.
A seventh potential mechanism relates to a known quirk of homocysteine synthesis and metabolism. The equilibrium of the interconversion between SAH and homocysteine (catalyzed by SAH hydrolase) actually favors SAH synthesis (Figure 1). In vivo, this reaction proceeds toward homocysteine synthesis because of product removal, i.e., the efficient metabolism of homocysteine back to methio-nine or through cystathionine synthesis. However, when there is a block in homocysteine metabolism, as occurs in the genetic defects, B vitamin deficiencies, and other causes delineated above, homocys-teine accumulates intracellularly. Consequently, SAH also accumulates within cells. The significance of this phenomenon is that SAH is a feedback inhibitor of all SAM-dependent methylation reactions. Therefore, hyperhomocysteinemia may cause or contribute to vascular disease through SAHmediated inhibition of methylation.
Another area that is receiving increasing attention is the relationship between homocysteine, nitric oxide, and endothelial function. One of the roles of nitric oxide is as a vasodilator. Homocysteine has been shown to be an inhibitor of nitric oxide synthesis, and thus can inhibit vasodilatation. This has led to the hypothesis that hyperhomocysteinemia, by inhibiting nitric oxide synthesis, impairs the ability of the vascular endothelium to maintain homeostasis of vascular tone. This in turn may directly or indirectly increase susceptibility to vascular insults, thus promoting atherosclerosis and thrombosis.
The search for the definitive pathogenetic mechanism implicating homocysteine as a cause of vascular disease continues, and it is recognized that several mechanisms may contribute synergistically. However, some have questioned whether homocysteine is a cause of vascular disease, or simply a consequence.
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