Reactive oxygen species modulate HIF-1 mediated PAI-1 expression: involvement of the GTPase Rac1

Agnes Görlach; Utta Berchner-Pfannschmidt; Christoph Wotzlaw; Robbert H. Cool; Joachim Fandrey; Helmut Acker; Kurt Jungermann; Thomas Kietzmann

doi:10.1055/s-0037-1613480

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2003; 89(05): 926-935
DOI: 10.1055/s-0037-1613480

Cellular Proteolysis and Oncology

Schattauer GmbH

Reactive oxygen species modulate HIF-1 mediated PAI-1 expression: involvement of the GTPase Rac1

Authors

Agnes Görlach

¹Experimentelle Kinderkardiologie, Deutsches Herzzentrum München an der Technischen Universität München, Munich, Germany
Utta Berchner-Pfannschmidt

²Max-Planck-Institut für Molekulare Physiologie, Dortmund, Germany
Christoph Wotzlaw

²Max-Planck-Institut für Molekulare Physiologie, Dortmund, Germany
Robbert H. Cool

²Max-Planck-Institut für Molekulare Physiologie, Dortmund, Germany
Joachim Fandrey

³Institut für Physiologie, Universität Essen, Essen, Germany
Helmut Acker

²Max-Planck-Institut für Molekulare Physiologie, Dortmund, Germany
Kurt Jungermann

⁴Institut für Biochemie und Molekulare Zellbiologie, Georg-August-Universität, Göttingen, Germany

^†deceased May 10, 2002
Thomas Kietzmann

⁴Institut für Biochemie und Molekulare Zellbiologie, Georg-August-Universität, Göttingen, Germany

Abstract

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Summary

The hypoxia-inducible transcription factor HIF-1 mediates upregulation of plasminogen activator inhibitor-1 (PAI-1) expression under hypoxia. Reactive oxygen species (ROS) have also been implicated in PAI-1 gene expression. However, the role of ROS in HIF-1-mediated regulation of PAI-1 is not clear. We therefore investigated the role of the GTPase Rac1 which modulates ROS production in the pathway leading to HIF-1 and PAI-1 induction.

Overexpression of constitutively activated (RacG12V) or dominant-negative (RacT17N) Rac1 increased or decreased, respectively, ROS production. In RacG12V-expressing cells, PAI-1 mRNA levels as well as HIF-1α nuclear presence were reduced under normoxia and hypoxia whereas expression of RacT17N resulted in opposite effects. Treatment with the antioxidant pyrrolidinedithiocarbamate or coexpression of the redox factor-1 restored HIF-1 and PAI-1 promoter activity in RacG12V-cells. In contrast, NFκB activation was enhanced in RacG12V-cells, but abolished by RacT17N. Thus, these findings suggest a mechanism explaining modified fibrinolysis and tissue remodeling in an oxidized environment.

Keywords

PAI-1 - Rac1 - reactive oxygen species - hypoxia - fibrinolysis - thrombosis

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References

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