Reactive oxygen species modulate HIF-1 mediated PAI-1 expression: involvement of the GTPase Rac1
| Autor: | Görlach A, Berchner-Pfannschmidt U, Wotzlaw C, Rh, Cool, Joachim Fandrey, Acker H, Jungermann K, Kietzmann T |
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| Jazyk: | Dutch; Flemish |
| Rok vydání: | 2003 |
| Předmět: |
Cell Nucleus
Male rac1 GTP-Binding Protein Mutation Missense NF-kappa B Nuclear Proteins Hematology Hypoxia-Inducible Factor 1 alpha Subunit Transfection Rats DNA-Binding Proteins Gene Expression Regulation Plasminogen Activator Inhibitor 1 Hepatocytes Animals Hypoxia-Inducible Factor 1 RNA Messenger Rats Wistar Hypoxia Reactive Oxygen Species Transcription Factors |
| Zdroj: | Journal of Thrombosis and Haemostasis, 89(5), 926-935. Wiley Europe PubMed Central |
| ISSN: | 1538-7836 |
| Popis: | SummaryThe 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. |
| Databáze: | OpenAIRE |
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