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Blood, Vol. 96 No. 3 (August 1), 2000:
pp. 966-972
Induction of monocyte tissue factor expression by
homocysteine: a possible mechanism for thrombosis
Annu Khajuria and
Donald S. Houston
From the Manitoba Institute of Cell Biology and the Department of
Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
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 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, 2-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
O2 Radicals, respectively) were unable to
block the expression of tissue factor induced by homocysteine, as was a
5-fold excess of the reducing agent 2-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.
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