Inhibition of endothelial cell thromboresistance by homocysteine

Homocysteine (HC) is a highly reactive thiol intermediate in amino acid met abolism, which can modify the function of endothelial cells in a myriad of ways. In vitro, homocysteine can inhibit the thromboresistance properties o f the endothelial cell by induction of procoagulant factors, inactivation o f natural anticoagulant systems, and suppression of vasodilatory and platel et-modulating factors. HC also inhibits the fibrinolytic system by impairin g the ability of the endothelial cell to bind tissue plasminogen activator (t-PA), by interacting directly with the t-PA binding "tail" domain of its endothelial cell receptor, annexin II. Moreover, HC influences endothelial cell gene expression as exemplified by induction of the elongation factor-1 . family of polypeptides, which promote polypeptide chain elongation during mRNA translation. Induction of EF-1 subunits alpha, beta, gamma and delta by homocysteine is associated with increased turnover of at least one free thiol-containing protein, suggesting that up-regulation of these subunits m ay represent a mechanism for replacement of damaged or modified proteins. A more complete understanding of the diverse effects of homocysteine on endo thelial cell function may provide important clues to the precise role homoc ysteine may play in the initiation and progression of vascular disease.