Monocyte plasminogen activator inhibitor 2 (PAI-2) inhibits u-PA-mediated fibrin clot lysis and is cross-linked to fibrin.
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.
Ritchie
H
H
Department of Molecular and Cell Biology, University of Aberdeen, UK. h.ritchie@abdn.ac.uk
Robbie
L A
LA
Kinghorn
S
S
Exley
R
R
Booth
N A
NA
D002478:Cells, Cultured; D003432:Cross-Linking Reagents; D005337:Fibrin / Q000378:metabolism*; D005342:Fibrinolysis / Q000187:drug effects; D006801:Humans; D009000:Monocytes / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism; D017396:Plasminogen Activator Inhibitor 2 / Q000378:metabolism* / Q000494:pharmacology; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
D003432:Cross-Linking Reagents; D010455:Peptides; D017396:Plasminogen Activator Inhibitor 2; D005337:Fibrin; D014568:Urokinase-Type Plasminogen Activator