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Vol. 19, Issue 1, 86-94, January 2008

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Hypoxia-inducible Factor-1 Stabilization in Nonhypoxic Conditions: Role of Oxidation and Intracellular Ascorbate Depletion

Elisabeth L. Pagé^*, Denise A. Chan, Amato J. Giaccia, Mark Levine, and Darren E. Richard^*

*Centre de recherche de L'Hôtel-Dieu de Québec, Department of Medicine, Université Laval, Québec, QC, G1R 2J6, Canada; Center for Clinical Science Research, Department of Radiation Oncology, Stanford University, Stanford, CA 94305; and Molecular and Clinical Nutrition Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892

Submitted June 27, 2007; Revised September 18, 2007; Accepted October 10, 2007
Monitoring Editor: J. Silvio Gutkind

Hypoxia-inducible factor-1 (HIF-1) is a decisive element for the transcriptional regulation of many genes induced under low oxygen conditions. Under normal oxygen conditions, HIF-1, the active subunit of HIF-1, is hydroxylated on proline residues by specific HIF prolyl-hydroxylases, leading to ubiquitination and degradation by the proteasome. In hypoxia, hydroxylation and ubiquitination are blocked and HIF-1 accumulates in cells. Recent studies have shown that in normal oxygen conditions G-protein–coupled receptor agonists, including angiotensin (Ang) II and thrombin, potently induce and activate HIF-1 in vascular smooth muscle cells. The current study identifies HIF-1 protein stabilization as a key mechanism for HIF-1 induction by Ang II. We show that hydroxylation on proline 402 is altered by Ang II, decreasing pVHL binding to HIF-1 and allowing HIF-1 protein to escape subsequent ubiquitination and degradation mechanisms. We show that HIF-1 stability is mediated through the Ang II–mediated generation of hydrogen peroxide and a subsequent decrease in ascorbate levels, leading to decreased HIF prolyl-hydroxylase activity and HIF-1 stabilization. These findings identify novel and intricate signaling mechanisms involved in HIF-1 complex activation and will lead to the elucidation of the importance of HIF-1 in different Ang II–related cell responses.

Address correspondence to: Darren E. Richard (darren.richard{at}crhdq.ulaval.ca)

Abbreviations used: Ang II, angiotensin II; HIF, hypoxia-inducible factor; HRE, hypoxic response element; GPCR, G-protein–coupled receptor; ODDD, oxygen-dependent degradation domain; PHD, HIF prolyl-hydroxylases; pVHL, von Hippel-Lindau protein; ROS, reactive oxygen species; VEGF, vascular endothelial growth factor; VSMCs, vascular smooth muscle cells.

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