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

A. Gorlach, U. Berchner-Pfannschmidt, C. Wotzlaw, Robbert Cool, J. Fandrey, H. Acker, K Jungermann, T. Kietzmann

    OnderzoeksoutputAcademicpeer review

    74 Citaten (Scopus)

    Samenvatting

    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-alpha nuclear presence were reduced under normoxia and hypoxia whereas expression of RacT17N resulted in opposite effects. Treatment with the antioxidant pyr-rolidinedithiocarbamate or coexpression of the redox factor-1 restored HIF-1 and PAI-1 promoter activity in RacG12V-cells. In contrast, NFkappaB 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
    Originele taal-2Dutch
    Pagina's (van-tot)926 - 935
    TijdschriftJournal of Thrombosis and Haemostasis
    Volume89
    Nummer van het tijdschrift5
    StatusPublished - 2003

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