Journal
MOLECULAR BIOLOGY OF THE CELL
Volume 19, Issue 1, Pages 86-94Publisher
AMER SOC CELL BIOLOGY
DOI: 10.1091/mbc.E07-06-0612
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Funding
- Canadian Institutes of Health Research (CIHR) [MOP-49609]
- Heart and Stroke Foundations of Quebec and Canada
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [ZIADK054506, Z01DK054506] Funding Source: NIH RePORTER
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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-1 alpha, 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-1 alpha 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-1 alpha 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-1 alpha and allowing HIF-1 alpha protein to escape subsequent ubiquitination and degradation mechanisms. We show that HIF-1 alpha 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-1 alpha 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.
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