Reactive oxygen species modulate HIF-1 mediated PAI-1 expression: involvement of the GTPase Rac1.
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.
Experimentelle Kinderkardiologie, Deutsches Herzzentrum Müchen and der Technischen Universität Müchen, Munich, Germany. goerlach@dhm.mhn.de
Agnes
A
Görlach
Utta
U
Berchner-Pfannschmidt
Christoph
C
Wotzlaw
Robbert H
RH
Cool
Joachim
J
Fandrey
Helmut
H
Acker
Kurt
K
Jungermann
Thomas
T
Kietzmann
D000818:Animals; D002467:Cell Nucleus / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000032:analysis / Q000096:biosynthesis* / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D022781:Hepatocytes; D000860:Hypoxia / Q000378:metabolism; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008297:Male; D020125:Mutation, Missense; D016328:NF-kappa B / Q000032:analysis / Q000378:metabolism; D009687:Nuclear Proteins / Q000032:analysis / Q000096:biosynthesis* / Q000502:physiology; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism / Q000494:pharmacology*; D014157:Transcription Factors; D014162:Transfection; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000502:physiology*
D004268:DNA-Binding Proteins; C497444:Hif1a protein, rat; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016328:NF-kappa B; D009687:Nuclear Proteins; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D020830:rac1 GTP-Binding Protein