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Vol. 18, Issue 12, 4691-4697, December 2007

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Hypoxia Up-Regulates Hypoxia-Inducible Factor-1 Transcription by Involving Phosphatidylinositol 3-Kinase and Nuclear Factor B in Pulmonary Artery Smooth Muscle Cells

Rachida S. BelAiba^*, Steve Bonello^*, Christian Zähringer^*, Stefanie Schmidt^*, John Hess^*, Thomas Kietzmann, and Agnes Görlach^*

*Experimental Pediatric Cardiology, Department of Pediatric Cardiology and Congenital Heart Disease, German Heart Center Munich at the Technical University Munich, D-80636 Munich, Germany; and Faculty of Chemistry/Biochemistry, University of Kaiserslautern, D-67663 Kaiserslautern, Germany

Submitted April 30, 2007; Revised August 7, 2007; Accepted September 17, 2007
Monitoring Editor: Carl-Henrik Heldin

The oxygen sensitive -subunit of the hypoxia-inducible factor-1 (HIF-1) is a major trigger of the cellular response to hypoxia. Although the posttranslational regulation of HIF-1 by hypoxia is well known, its transcriptional regulation by hypoxia is still under debate. We, therefore, investigated the regulation of HIF-1 mRNA in response to hypoxia in pulmonary artery smooth muscle cells. Hypoxia rapidly enhanced HIF-1 mRNA levels and HIF-1 promoter activity. Furthermore, inhibition of the phosphatidylinositol 3-kinase (PI3K)/AKT but not extracellular signal-regulated kinase 1/2 pathway blocked the hypoxia-dependent induction of HIF-1 mRNA and HIF-1 promoter activity, suggesting involvement of a PI3K/AKT-regulated transcription factor. Interestingly, hypoxia also induced nuclear factor-B (NFB) nuclear translocation and activity. In line, expression of the NFB subunits p50 and p65 enhanced HIF-1 mRNA levels, whereas blocking of NFB by an inhibitor of nuclear factor-B attenuated HIF-1 mRNA induction by hypoxia. Reporter gene assays revealed the presence of an NFB site within the HIF-1 promoter, and mutation of this site abolished induction by hypoxia. In line, gel shift analysis and chromatin immunoprecipitation confirmed binding of p50 and p65 NFB subunits to the HIF-1 promoter under hypoxia. Together, these findings provide a novel mechanism in which hypoxia induces HIF-1 mRNA expression via the PI3K/AKT pathway and activation of NFB.

Address correspondence to: Agnes Görlach (goerlach{at}dhm.mhn.de).

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