Homocysteine is an intermediate, thiol-containing amino acid produced in the transsulfuration pathway that converts methionine to cysteine. It accumulates in plasma and intracellularly in the inborn error of metabolism, homocystinuria, and in homocyst(e)inemia of either inherited or acquired etiology. Recent data have strongly implicated homocysteine as an independent risk factor in thrombosis and atherosclerosis involving coronary, cerebral, and peripheral arteries. In addition, homocyst(e)inemia may play a role in the pathogenesis of deep vein thrombosis. Several studies have demonstrated that exogenously applied homocysteine can abrogate many of the thromboresistance properties of cultured endothelial cells, and that diet-induced homocyst(e)inemia in an animal model resulted in abnormal vasoreactivity. The mechanism for these varied effects, however, are not well understood. This proposal pland to examine, at the molecular level, the effects of exogenously-applied and endogenously-produced homocysteine on several aspects of endothelial cell function. Using recombinant chimeric proteins and mutational analysis, it is planned to delineate the mechanism by which homocysteine may selectively block tissue plasminogen activator binding to the """"""""tail"""""""" domain of its catalytic receptor, annexin II. The investigators will study the effect of homocysteine on migration and matrix-directed organization of normal, heterozygous, and cystathionine Beta-synthase null deletion endothelial cells, and explore its influence in models of aniogenesis. They will examine the effect of homocysteine on the half-life of thiol containing proteins such as annexin II, and the endothelial cell translational response to altered protein turnover. Finally, they plan to define the pathway by which homocysteine induces transcriptional up-regulation of a family of translational regulatory proteins, elongation factor-1alpha, Beta and 0.
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| Deora, Arunkumar B; Kreitzer, Geri; Jacovina, Andrew T et al. (2004) An annexin 2 phosphorylation switch mediates p11-dependent translocation of annexin 2 to the cell surface. J Biol Chem 279:43411-8 |
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| Hajjar, K A; Mauri, L; Jacovina, A T et al. (1998) Tissue plasminogen activator binding to the annexin II tail domain. Direct modulation by homocysteine. J Biol Chem 273:9987-93 |
