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Hypoxia-inducible factor-1alpha stabilization in nonhypoxic conditions: role of oxidation and intracellular ascorbate depletion.

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.

Pubmed ID: 17942596


  • PagĂ© EL
  • Chan DA
  • Giaccia AJ
  • Levine M
  • Richard DE


Molecular biology of the cell

Publication Data

January 3, 2008

Associated Grants


Mesh Terms

  • 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