title: Pathogenesis of Hyperhomocysteinemia-New Insights.
abstract: Mild to moderately elevated levels of homocysteine (Hey) in plasma, denoted as hyperhomocysteinemia, is emerging as a prevalent and strong risk factor for atherosclerotic vascular disease in coronary, cerebral and peripheral vessels, as well as for arterial and venous thromboembolism. Despite its clinical significance, the molecular mechanism of homocysteine's effects is not yet clearly defined. Most of the effects of homocysteine that have been demonstrated in vitro, affecting endothelial function have been attributed to the oxidant reactivity of this molecule, which is shown to affect the vasoregulatory and thrombotic/fibrinolytic function of endothelium. However, the relevance of these observations to the clinical situations is questionable, since excessively high concentrations of homocysteine are used in most of the experiments. We have observed that homocysteine, at physiologically relevant concentrations, specifically induces the expression of tissue factor by monocytes, and a non-specific redox effect is not involved. Tissue factor expression by monocytes is mediated by increased intracellular concentrations of the metabolic intermediate, S-adenosylhomocysteine, which is a potent inhibitor of methyl transferases. These studies suggest that tissue factor expression by circulating monocytes by intracellular perturbations may be a plausible mechanism by which homocysteine may induce thrombosis.
authors.affiliation: a Department of Clinical Chemistry, Health Sciences Centre , 820 Sherbrook Street, Winnipeg , Canada MB R3A 1R9.
authors.forename: A
authors.initials: A
authors.lastname: Khajuria
authors.affiliation: b Manitoba Institute of Cell Biology , 675 Mc Dermot Avenue, Winnipeg , Canada MB R3E 0V9.
authors.forename: D S
authors.initials: DS
authors.lastname: Houston
keywords: Homocysteine; Hyperhomocysteinemia; Monocytes; S-adenosyl homocysteine; Tissue factor