Reactive oxygen species activate the HIF-1α promoter via a functional NFκB site

被引:540
作者
Bonello, Steve
Zahringer, Christian
BelAiba, Rachida S.
Djordjevic, Talija
Hess, John
Michiels, Carine
Kietzmann, Thomas
Goerlach, Agnes
机构
[1] Tech Univ Munich, German Heart Ctr, Dept Pediat Cardiol & Congenital Heart Dis, D-80636 Munich, Germany
[2] Univ Namur, Lab Biochem & Cellular Biol, Namur, Belgium
[3] Univ Kaiserslautern, Fac Chem Biochem, D-67663 Kaiserslautern, Germany
关键词
hypoxia-inducible factor; NADPH oxidase; nuclear factor kappa B; reactive oxygen species; thrombin; HYPOXIA-INDUCIBLE FACTOR; SMOOTH-MUSCLE-CELLS; TUMOR-NECROSIS-FACTOR; FACTOR-I; OXIDATIVE STRESS; DEPENDENT REGULATION; GENE-TRANSCRIPTION; HYDROGEN-PEROXIDE; FACTOR EXPRESSION; INHIBITOR-1; GENE;
D O I
10.1161/01.ATV.0000258979.92828.bc
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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-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 NF-kappa B and HIF-1 alpha. The reactive oxygen species-mediated HIF-1 alpha induction occurred on the transcriptional level and was dependent on NF-kappa B. Transfection experiments with wild-type or mutant HIF-1 alpha promoter constructs revealed the presence of a yet unidentified NF-kappa B binding element. Gel shift analyses and chromatin immunoprecipitation verified binding of NF-kappa B to this site. Furthermore, reactive oxygen species enhanced expression of plasminogen activator inhibitor-1, which was prevented by dominant-negative I kappa 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 alpha and NF-kappa B, implicating an important pathophysiological role of this novel pathway in disorders associated with elevated levels of reactive oxygen species.
引用
收藏
页码:755 / 761
页数:7
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