on February 1, 2007
Published online before print February 1, 2007, doi: 10.1161/01.ATV.0000258979.92828.bc
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Submitted on July 18, 2006
Accepted on January 12, 2007
Reactive Oxygen Species Activate the HIF-1
Promoter Via a Functional NF
B Site
Steve Bonello ;
From Experimental Pediatric Cardiology (S.b., C.Z., R.S.B., T.D., J.H., A.G.), Department of Pediatric Cardiology and Congenital Heart Disease, German Heart Center Munich at the TU Munich, Germany; Laboratory of Biochemistry and Cellular Biology (C.M.), University of Namur, Belgium; Faculty of Chemistry/Biochemistry (T.K.), University of Kaiserslautern, Germany.
* To whom correspondence should be addressed. E-mail: goerlach{at}dhm.mhn.de.
Objective--Reactive oxygen species have been implicated as signaling molecules modulating the activity of redox-sensitive transcription factors such as nuclear factor kappa B. Recently, the transcription factor hypoxia-inducible factor-1 (HIF-1), known to mediate gene expression by hypoxia, has been found to be also activated by nonhypoxic factors in a redox-sensitive manner. We therefore aimed to elucidate the link between these 2 important redox-sensitive transcription factors.
Methods and Results--In pulmonary artery smooth muscle cells, reactive oxygen species generated either by exogenous H2O2 or by a NOX4-containing NADPH oxidase stimulated by thrombin activated or induced nuclear factor kappa B and HIF-1
. The reactive oxygen species-mediated HIF-1 induction occurred on the transcriptional level and was dependent on nuclear factor kappa B. Transfection experiments with wild-type or mutant HIF-1 promoter constructs revealed the presence of a yet unidentified nuclear factor kappa B binding element. Gel shift analyses and chromatin immunoprecipitation verified binding of nuclear factor kappa B to this site. Furthermore, reactive oxygen species enhanced expression of plasminogen activator inhibitor-1, which was prevented by dominant-negative I
B or mutation of the HIF-1 binding site within the plasminogen activator inhibitor-1 promoter.
Conclusion--These findings show for the first time to our knowledge that reactive oxygen species directly link HIF-1 and nuclear factor kappa B, implicating an important pathophysiological role of this novel pathway in disorders associated with elevated levels of reactive oxygen species.
Key words: hypoxia-inducible factor • NADPH oxidase • nuclear factor kappa B • reactive oxygen species • thrombin
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