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Hypoxia-inducible factor-1 (HIF-1) is a key transcription factor for responses to low oxygen. Different nonhypoxic stimuli, including hormones and growth factors, are also important HIF-1 activators in the vasculature. Angiotensin II (Ang II), the main effecter hormone in the renin-angiotensin system, is a potent HIF-1 activator in vascular smooth muscle cells (VSMCs). HIF-1 activation by Ang II involves intricate mechanisms of HIF-1α transcription, translation, and protein stabilization. Additionally, the generation of reactive oxygen species (ROS) is essential for HIF-1 activation during Ang II treatment. However, the role of the different VSMC ROS generators in HIF-1 activation by Ang II remains unclear. This work aims at elucidating this question. Surprisingly, repression of NADPH oxidase-generated ROS, using Vas2870, a specific inhibitor or a p22(phox) siRNA had no significant effect on HIF-1 accumulation by Ang II. In contrast, repression of mitochondrial-generated ROS, by complex III inhibition, by Rieske Fe-S protein siRNA, or by the mitochondrial-targeted antioxidant SkQ1, strikingly blocked HIF-1 accumulation. Furthermore, inhibition of mitochondrial-generated ROS abolished HIF-1α protein stability, HIF-1-dependent transcription and VSMC migration by Ang II. A large number of studies implicate NADPH oxidase-generated ROS in Ang II-mediated signaling pathways in VSMCs. However, our work points to mitochondrial-generated ROS as essential intermediates for HIF-1 activation in nonhypoxic conditions.

Original publication

DOI

10.1091/mbc.e10-01-0025

Type

Journal article

Journal

Molecular biology of the cell

Publication Date

09/2010

Volume

21

Pages

3247 - 3257

Addresses

Centre de recherche du CHUQ, L'Hôtel-Dieu de Québec, Department of Molecular Biology, Medical Biochemistry and Pathology, Université Laval, Québec, QC, G1R 2J6, Canada.

Keywords

Muscle, Smooth, Vascular, Cells, Cultured, Mitochondria, Myocytes, Smooth Muscle, Animals, Rats, Rats, Wistar, Reactive Oxygen Species, Methacrylates, Polyenes, Thiazoles, Electron Transport Complex III, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Angiotensin II, RNA, Small Interfering, Anti-Bacterial Agents, Antifungal Agents, Male, Hypoxia-Inducible Factor 1, NADPH Oxidases