Induction of monocyte tissue factor expression by homocysteine: a possible mechanism for thrombosis

Moderately elevated plasma homocysteine levels are an important independent risk factor for arterial and venous thrombosis and for atherosclerosis. Some investigators have proposed that homocysteine's effects result from oxidant injury to the vascular endothelium or from an alteration in endothelial function. However, homocysteine may have other cellular targets. We now report that homocysteine, at physiologically relevant concentrations, induces the expression of tissue factor by monocytes, In response to homocysteine, monocytes express procoagulant activity in a dose-dependent Introduction and a time-dependent manner. This activity is attributable to tissue factor because it was dependent on factor VII and blocked by anti-tissue factor antibodies. Tissue factor mRNA levels were also increased in monocytes after homocysteine treatment. The effect was found to be specific because analogues of homocysteine (homocystine and homocysteine thiolactone) did not mimic homocysteine's activity, nor did other thiol compounds (cysteine, P-mercaptoethanol, dithiothreitol). On the other hand, methionine, the metabolic precursor of homocysteine, was active though less potent than homocysteine, Catalase and superoxide dismutase (scavengers of H2O2 and O-2(-) Radicals, respectively) were unable to block the expression of tissue factor induced by homocysteine, as was a 5-fold excess of the reducing agent P-mercaptoethanol, We conclude that the induction of tissue factor expression by circulating monocytes is a plausible mechanism by which homocysteine may induce thrombosis and that a nonspecific redox process is not involved. (C) 2000 by The American Society of Hematology.