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.

journal_name

Endocrinology

journal_title

Endocrinology

authors

Lauzier MC,Pagé EL,Michaud MD,Richard DE

doi

10.1210/en.2007-0285

subject

Has Abstract

pub_date

2007-08-01 00:00:00

pages

4023-31

issue

8

eissn

0013-7227

issn

1945-7170

pii

en.2007-0285

journal_volume

148

pub_type

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