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

H Ritchie, L A Robbie, S Kinghorn, R Exley, N A Booth

Research output: Contribution to journalArticle

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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 PAT-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 Gin 83 and 86 as residues important in crosslinking. This study defines a mechanism by which PAI-I, is localized to fibrin, where it acts as an effective inhibitor of u-PA-mediated fibrinolysis.

Original languageEnglish
Pages (from-to)96-103
Number of pages8
JournalJournal of Thrombosis and Haemostasis
Volume81
Publication statusPublished - 1999

Keywords

  • TUMOR-NECROSIS-FACTOR
  • PERIPHERAL-BLOOD MONOCYTES
  • FACTOR-XIIIA
  • HAEMENTERIA-GHILIANII
  • PEPTIDIC INHIBITOR
  • ENDOTHELIAL-CELLS
  • IN-VITRO
  • TYPE-2
  • LINKING
  • TRANSGLUTAMINASE

Cite this

Monocyte plasminogen activator inhibitor 2 (PAI-2) inhibits u-PA-mediated fibrin clot lysis and is cross-linked to fibrin. / Ritchie, H ; Robbie, L A ; Kinghorn, S ; Exley, R ; Booth, N A .

In: Journal of Thrombosis and Haemostasis, Vol. 81, 1999, p. 96-103.

Research output: Contribution to journalArticle

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T1 - Monocyte plasminogen activator inhibitor 2 (PAI-2) inhibits u-PA-mediated fibrin clot lysis and is cross-linked to fibrin

AU - Ritchie, H

AU - Robbie, L A

AU - Kinghorn, S

AU - Exley, R

AU - Booth, N A

PY - 1999

Y1 - 1999

N2 - 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 PAT-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 Gin 83 and 86 as residues important in crosslinking. This study defines a mechanism by which PAI-I, is localized to fibrin, where it acts as an effective inhibitor of u-PA-mediated fibrinolysis.

AB - 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 PAT-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 Gin 83 and 86 as residues important in crosslinking. This study defines a mechanism by which PAI-I, is localized to fibrin, where it acts as an effective inhibitor of u-PA-mediated fibrinolysis.

KW - TUMOR-NECROSIS-FACTOR

KW - PERIPHERAL-BLOOD MONOCYTES

KW - FACTOR-XIIIA

KW - HAEMENTERIA-GHILIANII

KW - PEPTIDIC INHIBITOR

KW - ENDOTHELIAL-CELLS

KW - IN-VITRO

KW - TYPE-2

KW - LINKING

KW - TRANSGLUTAMINASE

M3 - Article

VL - 81

SP - 96

EP - 103

JO - Journal of Thrombosis and Haemostasis

JF - Journal of Thrombosis and Haemostasis

SN - 1538-7933

ER -