Monocyte Plasminogen Activator Inhibitor 2 (PAI-2) Inhibits u-PA-mediated Fibrin Clot Lysis and Is Cross-linked to Fibrin

Helen Ritchie; Linda A. Robbie; Seonag Kinghorn; Rachel Exley; Nuala A. Booth

doi:10.1055/s-0037-1614425

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 1999; 81(01): 96-103
DOI: 10.1055/s-0037-1614425

Review Article

Schattauer GmbH

Monocyte Plasminogen Activator Inhibitor 2 (PAI-2) Inhibits u-PA-mediated Fibrin Clot Lysis and Is Cross-linked to Fibrin

Helen Ritchie

¹From the Departments of Molecular and Cell Biology and, University of Aberdeen, Aberdeen, UK

,

Linda A. Robbie

¹From the Departments of Molecular and Cell Biology and, University of Aberdeen, Aberdeen, UK

²From the Departments of Medicine and Therapeutics, University of Aberdeen, Aberdeen, UK

,

Seonag Kinghorn

¹From the Departments of Molecular and Cell Biology and, University of Aberdeen, Aberdeen, UK

,

Rachel Exley

¹From the Departments of Molecular and Cell Biology and, University of Aberdeen, Aberdeen, UK

,

Nuala A. Booth

¹From the Departments of Molecular and Cell Biology and, University of Aberdeen, Aberdeen, UK

› Institutsangaben

Abstract

Summary

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.

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