Monocyte plasminogen activator inhibitor 2 (PAI-2) inhibits u-PA-mediated fibrin clot lysis and is cross-linked to fibrin

Thromb Haemost. 1999 Jan;81(1):96-103.

Abstract

Plasminogen activator inhibitor 2 (PAI-2) is a major product of activated human monocytes. Here we show that monocytes inhibited u-PA- but not t-PA-mediated fibrinolysis, by secreting PAI-2 into an overlying fibrin clot. Extracts of arterial and venous human thrombi were found to contain active PAI-2. PAI-2 was cross-linked to fibrin in a reaction catalyzed by two major transglutaminases (TG), tissue TG and factor XIII. The activity of PAI-2 was not affected by such cross-linking. Cross-linking of PAI-2 to fibrin was inhibited by Tridegin, a specific inhibitor of TG, and also by EDTA and iodoacetamide. The use of competitive peptides mimicking the loop between helices C and D of PAI-2 identified Gln 83 and 86 as residues important in cross-linking. This study defines a mechanism by which PAI-2 is localized to fibrin, where it acts as an effective inhibitor of u-PA-mediated fibrinolysis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cells, Cultured
  • Cross-Linking Reagents
  • Fibrin / metabolism*
  • Fibrinolysis* / drug effects
  • Humans
  • Monocytes / metabolism*
  • Peptides / metabolism
  • Plasminogen Activator Inhibitor 2 / metabolism*
  • Plasminogen Activator Inhibitor 2 / pharmacology
  • Urokinase-Type Plasminogen Activator / metabolism*

Substances

  • Cross-Linking Reagents
  • Peptides
  • Plasminogen Activator Inhibitor 2
  • Fibrin
  • Urokinase-Type Plasminogen Activator