Role of nitric oxide in the regulation of HIF-1alpha expression during hypoxia

Am J Physiol Cell Physiol. 2002 Jul;283(1):C178-86. doi: 10.1152/ajpcell.00381.2001.


Hypoxia-inducible factor-1 (HIF-1), a heterodimeric transcription factor consisting of HIF-1alpha and HIF-1beta subunits, controls the expression of a large number of genes involved in the regulation of cellular responses to reduced oxygen availability. The oxygen-regulated subunit, HIF-1alpha, is stabilized in cells exposed to hypoxia. The regulation of hypoxic responses by nitric oxide (NO) is believed to have wide pathophysiological relevance, thus we investigated whether NO affects HIF-1 activation in hypoxic cells. Here we show that NO generated from NO donors prevented HIF-1alpha hypoxic accumulation in Hep 3B and PC-12 cells. Addition of a glutathione analog or peroxynitrite scavengers prevented the NO-induced inhibition of HIF-1alpha accumulation in both cell lines. Exposure to NO was associated with inhibition of mitochondrial electron transport and compensatory glycolysis, which maintained normal cellular ATP content. Succinate, a Krebs cycle intermediate and respiratory chain substrate, restored HIF-1alpha hypoxic induction in the cells, suggesting involvement of mitochondria in regulation of HIF-1alpha accumulation during hypoxia. Regulation of HIF-1alpha by NO is an additional important mechanism by which NO might modulate cellular responses to hypoxia in mammalian cells.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Hypoxia / physiology*
  • Electron Transport Complex I
  • Glutathione / analogs & derivatives*
  • Glutathione / pharmacology
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Mitochondria / metabolism
  • NADH, NADPH Oxidoreductases / metabolism
  • Nitric Oxide / pharmacology
  • Nitric Oxide / physiology*
  • Nitric Oxide Donors / pharmacology
  • PC12 Cells
  • Rats
  • S-Nitroso-N-Acetylpenicillamine / pharmacology
  • Succinic Acid / pharmacology
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / metabolism*
  • Triazenes / pharmacology
  • Tumor Cells, Cultured
  • Uric Acid / pharmacology


  • 1-hydroxy-2-oxo-3,3-bis(2-aminoethyl)-1-triazene
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Nitric Oxide Donors
  • Transcription Factors
  • Triazenes
  • Uric Acid
  • Nitric Oxide
  • S-Nitroso-N-Acetylpenicillamine
  • S-ethyl glutathione
  • Succinic Acid
  • NADH, NADPH Oxidoreductases
  • Electron Transport Complex I
  • Glutathione