Homocysteine-induced modulation of tissue plasminogen activator binding to its endothelial cell membrane receptor.
Endothelial cells impart thromboresistance to the blood vessel wall. As modulators of fibrinolytic activity, these cells synthesize and secrete tissue plasminogen activator (t-PA) as well as its physiologic inhibitor, plasminogen activator inhibitor-1. In addition, endothelial cells support membrane-associated assembly of plasminogen and tissue plasminogen activator. Recently, an M(r) approximately 40,000 protein expressed on endothelial cells has been shown to interact noncompetitively through disparate mechanisms with both t-PA and plasminogen, suggesting trimolecular assembly of enzyme, substrate, and receptor (Hajjar, K. A. 1991. J. Biol. Chem. 266:21962-21970). In the present study, treatment of cultured endothelial cells with DL-homocysteine was specifically associated with a selective reduction in cellular binding sites for t-PA. This 65% decrease in binding was associated with a 60% decrease in cell-associated t-PA activity. No change in affinity for t-PA or plasminogen or in the maximal number of binding sites for plasminogen was observed. Matrix-associated t-PA binding sites were not affected. These data suggest a new mechanism whereby homocysteine may perturb endothelial cell function, thus promoting a prothrombotic state at the surface of the blood vessel wall.
Hajjar
K A
KA
Department of Pediatrics, Cornell University Medical College, New York 10021.
D043424:Carboxypeptidase B; D002268:Carboxypeptidases / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006710:Homocysteine / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000378:metabolism*; D010959:Tissue Plasminogen Activator / Q000378:metabolism*; D014471:Umbilical Veins / Q000166:cytology
D008024:Ligands; D011956:Receptors, Cell Surface; D006710:Homocysteine; D002268:Carboxypeptidases; D043424:Carboxypeptidase B; C067262:PLAT protein, human; D010959:Tissue Plasminogen Activator