title: Differential regulation of hypoxia-inducible factor-1 through receptor tyrosine kinase transactivation in vascular smooth muscle cells.
abstract: 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-1alpha by protein stabilization, Ang II induced HIF-1alpha 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-1alpha 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.
authors.affiliation: Centre de Recherche de L'Hôtel-Dieu de Québec, 10 Rue McMahon, Québec, Canada G1R 2J6.
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Lauzier
authors.forename: Elisabeth L
authors.initials: EL
authors.lastname: Pagé
authors.forename: Maude D
authors.initials: MD
authors.lastname: Michaud
authors.forename: Darren E
authors.initials: DE
authors.lastname: Richard
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017382:Reactive Oxygen Species; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D017526:Receptor, IGF Type 1; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3