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Submitted on March 1, 2007
Accepted on May 9, 2007
Centre de recherche de L'Hôtel-Dieu de Québec and the Department of Medicine, Université Laval, Québec, QC, Canada
* To whom correspondence should be addressed. 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 (VSMC), 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 VSMC are the epidermal growth factor receptor (EGFR) and the insulin-like growth factor-1 receptor (IGF-1R). 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-1R is essential for HIF-1 protein translation through phosphatidylinositol 3-kinase/p70S6 kinase pathway activation and EGFR transactivation is implicated in HIF-1 complex activation through the stimulation of the p42/p44 mitogen-activated protein kinase 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.
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