title: Homocysteine, an atherogenic stimulus, reduces protein C activation by arterial and venous endothelial cells.
abstract: 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.
authors.affiliation: Division of Hematology/Oncology, University of Utah Medical Center, Salt Lake City 84132.
authors.forename: G M
authors.initials: GM
authors.lastname: Rodgers
authors.forename: M T
authors.initials: MT
authors.lastname: Conn
mesh_terms: D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology* / Q000378:metabolism / Q000648:ultrastructure; D006710:Homocysteine / Q000494:pharmacology*; D006801:Humans; D011486:Protein C / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism; D018179:Receptors, Thrombin
chemical_list: D011486:Protein C; D011956:Receptors, Cell Surface; D018179:Receptors, Thrombin; D006710:Homocysteine