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Homocysteine, an atherogenic stimulus, reduces protein C activation by
arterial and venous endothelial cells
GM Rodgers and MT Conn
Division of Hematology/Oncology, University of Utah Medical Center, Salt
Lake City 84132.
Elevated blood levels of homocysteine are associated with atherosclerosis
and thrombotic disease. We previously reported that treatment of cultured
endothelial cells with homocysteine increased endogenous factor V activity
by activation of the cofactor. Because endothelial cell-associated factor
Va would be regulated by the protein C mechanism, the ability of
homocysteine-treated arterial and venous endothelial cells to activate
protein C was investigated. Both arterial and venous endothelial cells
activated protein C; 0.6 mmol/L homocysteine reduced endothelial cell
protein C activation by 12%. Maximal inhibition (90%) of protein C
activation occurred with 7.5 to 10 mmol/L homocysteine after 6 to 9 hours
of incubation. Metabolism of homocysteine was not accelerated by cultured
endothelial cells. Investigation of the mechanism(s) by which homocysteine
reduced protein C activation indicated that the metabolite did not induce
an inhibitor to activated protein C, but in low concentrations acted as a
competitive inhibitor to thrombin. These data suggest that perturbation of
the vascular endothelial cell protein C mechanism by homocysteine may
contribute to the thrombotic tendency seen in patients with elevated blood
levels of this metabolite.
Volume 75,
Issue 4,
pp. 895-901,
02/15/1990
Copyright © 1990 by The American Society of Hematology
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