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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:755.)
© 2007 American Heart Association, Inc.

Vascular Biology

Reactive Oxygen Species Activate the HIF-1 Promoter Via a Functional NFB Site

Steve Bonello; Christian Zähringer; Rachida S. BelAiba; Talija Djordjevic; John Hess; Carine Michiels; Thomas Kietzmann; Agnes Görlach

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.

Correspondence to Agnes Görlach, MD, Experimental Pediatric Cardiology, Department of Pediatric Cardiology and Congenital Heart Disease, German Heart Center Munich at the TU Munich, Lazarettstr. 36, D-80636 Munich, Germany. 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 (NF-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 NF-B and HIF-1. The reactive oxygen species-mediated HIF-1 induction occurred on the transcriptional level and was dependent on NF-B. Transfection experiments with wild-type or mutant HIF-1 promoter constructs revealed the presence of a yet unidentified NF-B binding element. Gel shift analyses and chromatin immunoprecipitation verified binding of NF-B to this site. Furthermore, reactive oxygen species enhanced expression of plasminogen activator inhibitor-1, which was prevented by dominant-negative IB 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 NF-B, implicating an important pathophysiological role of this novel pathway in disorders associated with elevated levels of reactive oxygen species.

ROS generated by exogenous H₂O₂ or by a NOX4-containing NADPH oxidase stimulated by thrombin, transcriptionally induced HIF-1 via a novel NFB binding site in the HIF-1 promoter. Thus, ROS directly link these 2 major transcription factors, implicating an important role of this novel pathway in disorders associated with oxidative stress.

Key Words: hypoxia-inducible factor • NADPH oxidase • nuclear factor kappa B • reactive oxygen species • thrombin

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