This Article Full Text Full Text (PDF) All Versions of this Article: 148/8/4023    most recent Author Manuscript (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lauzier, M.-C. Articles by Richard, D. E. Search for Related Content PubMed PubMed Citation Articles by Lauzier, M.-C. Articles by Richard, D. E.

Differential Regulation of Hypoxia-Inducible Factor-1 through Receptor Tyrosine Kinase Transactivation in Vascular Smooth Muscle Cells

Centre de Recherche de L’Hôtel-Dieu de Québec and the Department of Medicine, Université Laval, Québec, Québec, Canada G1R 2J6

Address all correspondence and requests for reprints to: Darren E. Richard, Centre de Recherche de L’Hôtel-Dieu de Québec, 10 Rue McMahon, Québec, Canada G1R 2J6. E-mail: darren.richard{at}crhdq.ulaval.ca.

Hypoxia-inducible factor-1 (HIF-1) is a decisive element for the transcriptional regulation of many genes expressed in hypoxic conditions. In vascular smooth muscle cells, the vasoactive hormone angiotensin II (Ang II) is a very potent inducer and activator of HIF-1. As opposed to hypoxia, which induces HIF-1 by protein stabilization, Ang II induced HIF-1 through transcriptional and translational mechanisms. Interestingly, a number of intracellular signaling events triggered by Ang II are mediated by the transactivation of receptor tyrosine kinases. The major receptor tyrosine kinases shown to be transactivated by Ang II in vascular smooth muscle cells are the epidermal growth factor receptor and the IGF-I receptor. In this study, we demonstrate that the transactivation of both these receptor tyrosine kinases is involved in HIF-1 complex activation by Ang II. More interestingly, this modulation of HIF-1 is at different degrees and through different pathways. Our results show that transactivation of IGF-I receptor is essential for HIF-1 protein translation through phosphatidylinositol 3-kinase/p70S6 kinase pathway activation, and epidermal growth factor receptor transactivation is implicated in HIF-1 complex activation through the stimulation of the p42/p44 MAPK pathway. Our results therefore show that Ang II-induced receptor tyrosine kinase transactivation is essential in both the induction and activation of HIF-1. These findings identify novel and intricate signaling mechanisms involved in HIF-1 complex activation.

This article has been cited by other articles:

				M.-C. Lauzier, G. A. Robitaille, D. A. Chan, A. J. Giaccia, and D. E. Richard (2R)-[(4-Biphenylylsulfonyl)amino]-N-hydroxy-3-phenylpropionamide (BiPS), a Matrix Metalloprotease Inhibitor, Is a Novel and Potent Activator of Hypoxia-Inducible Factors Mol. Pharmacol., July 1, 2008; 74(1): 282 - 288. [Abstract] [Full Text] [PDF]

				Y.-K. Park, D.-R. Ahn, M. Oh, T. Lee, E. G. Yang, M. Son, and H. Park Nitric Oxide Donor, ({+/-})-S-Nitroso-N-acetylpenicillamine, Stabilizes Transactive Hypoxia-Inducible Factor-1{alpha} by Inhibiting von Hippel-Lindau Recruitment and Asparagine Hydroxylation Mol. Pharmacol., July 1, 2008; 74(1): 236 - 245. [Abstract] [Full Text] [PDF]

				E. L. Page, D. A. Chan, A. J. Giaccia, M. Levine, and D. E. Richard Hypoxia-inducible Factor-1{alpha} Stabilization in Nonhypoxic Conditions: Role of Oxidation and Intracellular Ascorbate Depletion Mol. Biol. Cell, January 1, 2008; 19(1): 86 - 94. [Abstract] [Full Text] [PDF]