Homocysteine-induced modulation of tissue plasminogen activator binding to its endothelial cell membrane receptor

J Clin Invest. 1993 Jun;91(6):2873-9. doi: 10.1172/JCI116532.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Carboxypeptidase B
  • Carboxypeptidases / pharmacology
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism*
  • Dose-Response Relationship, Drug
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism*
  • Homocysteine / pharmacology*
  • Humans
  • Ligands
  • Receptors, Cell Surface / drug effects
  • Receptors, Cell Surface / metabolism*
  • Tissue Plasminogen Activator / metabolism*
  • Umbilical Veins / cytology


  • Ligands
  • Receptors, Cell Surface
  • Homocysteine
  • Carboxypeptidases
  • Carboxypeptidase B
  • PLAT protein, human
  • Tissue Plasminogen Activator