HIF-1alpha subunit and vasoactive HIF-1-dependent genes are involved in carbon monoxide-induced cerebral hypoxic stress response

Eur J Appl Physiol. 2008 Sep;104(1):95-102. doi: 10.1007/s00421-008-0776-9. Epub 2008 Jun 17.


Hypoxia-inducible transcription factor-1 (HIF-1) is the most important component of cellular and molecular adaptive responses to hypoxia. We aimed to analyze effects of systemic hypoxia and CO exposure on the oxygen-regulated alpha-subunit of HIF-1 and HIF-1-dependent vasoactive target genes in rat brain. Brains of adult Sprague-Dawley rats were investigated after incubation for 3 and 12 h under normoxia, hypoxia (8% O(2)) and CO 0.1% (n = 10 per group). Upon 3 h of exposure, hypoxia and CO-induced accumulation of HIF-1alpha protein in brain homogenates assessed by Western blot analysis. In contrast to hypoxia HIF-1alpha signals decreased markedly during 12 h-exposure to CO. By immunohistochemistry, intensive HIF-1alpha-positive staining was found in neurons of the cortex and hippocampus. Cerebral expression of vasoactive target genes adrenomedullin (ADM) and vascular endothelial growth factor (VEGF) showed up-regulation during both hypoxia and CO exposure indicating functional activation of HIF-1. Hypoxia increased ADM (P < 0.05) and VEGF mRNA levels within 3 h (P < 0.01) which persisted up to 12 h of exposure (ADM, P < 0.05; VEGF, P < 0.001). Similarly, CO inhalation led to early up-regulation of VEGF (3 h: P < 0.05; 12 h: P < 0.01), but a more delayed increase of ADM mRNA levels (3 h: n.s., 12 h: P < 0.01). We suggest that CO-induced oxygen deprivation is a potent stimulus to cerebral HIF-1-regulated hypoxic stress responses even though its effects are more transient than exposure to hypoxia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenomedullin / genetics
  • Adrenomedullin / metabolism*
  • Animals
  • Blotting, Western
  • Brain / metabolism*
  • Carbon Monoxide
  • Cerebrovascular Circulation
  • Disease Models, Animal
  • Hypoxia, Brain / chemically induced
  • Hypoxia, Brain / genetics
  • Hypoxia, Brain / metabolism*
  • Hypoxia, Brain / physiopathology
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Immunohistochemistry
  • Male
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Stress, Physiological / genetics
  • Stress, Physiological / metabolism*
  • Stress, Physiological / physiopathology
  • Time Factors
  • Up-Regulation
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism*


  • Hif1a protein, rat
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • RNA, Messenger
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, rat
  • Adrenomedullin
  • Carbon Monoxide