Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

Hypoxia-inducible factor-1 (HIF-1) is a decisive element for the transcriptional regulation of many genes induced under low oxygen conditions. Under normal oxygen conditions, HIF-1alpha, the active subunit of HIF-1, is hydroxylated on proline residues by specific HIF prolyl-hydroxylases, leading to ubiquitination and degradation by the proteasome. In hypoxia, hydroxylation and ubiquitination are blocked and HIF-1alpha accumulates in cells. Recent studies have shown that in normal oxygen conditions G-protein-coupled receptor agonists, including angiotensin (Ang) II and thrombin, potently induce and activate HIF-1 in vascular smooth muscle cells. The current study identifies HIF-1alpha protein stabilization as a key mechanism for HIF-1 induction by Ang II. We show that hydroxylation on proline 402 is altered by Ang II, decreasing pVHL binding to HIF-1alpha and allowing HIF-1alpha protein to escape subsequent ubiquitination and degradation mechanisms. We show that HIF-1alpha stability is mediated through the Ang II-mediated generation of hydrogen peroxide and a subsequent decrease in ascorbate levels, leading to decreased HIF prolyl-hydroxylase activity and HIF-1alpha stabilization. These findings identify novel and intricate signaling mechanisms involved in HIF-1 complex activation and will lead to the elucidation of the importance of HIF-1 in different Ang II-related cell responses.

Original publication

DOI

10.1091/mbc.e07-06-0612

Type

Journal article

Journal

Mol Biol Cell

Publication Date

01/2008

Volume

19

Pages

86 - 94

Keywords

Angiotensin II, Animals, Ascorbic Acid, Cell Hypoxia, Coenzymes, Half-Life, Humans, Hydrogen Peroxide, Hydroxylation, Hypoxia-Inducible Factor 1, alpha Subunit, Intracellular Space, Male, Oxidation-Reduction, Procollagen-Proline Dioxygenase, Protein Binding, Protein Processing, Post-Translational, Protein Structure, Tertiary, Rats, Rats, Wistar, Thermodynamics, Ubiquitination, Von Hippel-Lindau Tumor Suppressor Protein