Induction of hypoxia-inducible factor-1 (HIF-1) and its target genes following focal ischaemia in rat brain

Eur J Neurosci. 1999 Dec;11(12):4159-70. doi: 10.1046/j.1460-9568.1999.00845.x.


HIF-1 is a heterodimeric transcription factor, induced by hypoxia, that is composed of HIF-1alpha and HIF-1beta protein subunits. It binds to promoter/enhancer elements and stimulates the transcription of hypoxia-inducible target genes, including glucose transporter-1 and the glycolytic enzymes. Because HIF-1 activation might promote cell survival in hypoxic tissues, we studied the effect of permanent middle cerebral artery occlusion on the expression of HIF-1alpha, HIF-1beta and several HIF-1 target genes in adult rat brain. After focal ischaemia, mRNAs encoding HIF-1alpha, glucose transporter-1 and several glycolytic enzymes were up-regulated in the peri-infarct penumbra. This was observed by 7.5 h after the onset of ischaemia and increased further at 19 and 24 h. Regional cerebral blood flow was moderately decreased at 1 and 24 h after the ischaemia in areas of HIF-1 and HIF-1 target gene induction. Because hypoxia induces HIF-1 in other tissues, systemic hypoxia (6% O2 for 4.5 h) was also shown to increase HIF-1alpha protein expression in the adult rat brain. It is proposed that decreased blood flow to the penumbra decreases the supply of oxygen and that this induces HIF-1 and its target genes. This is the first study to show induction of HIF-1 after focal ischaemia in brain. Increased expression of HIF-1 target genes as a result of HIF-1 activation by hypoxia may contribute to tissue viability in the hypoxic/ischaemic penumbra by increasing glucose transport and glycolysis.

Publication types

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

MeSH terms

  • Animals
  • Brain / metabolism*
  • Cerebrovascular Circulation / physiology
  • DNA-Binding Proteins / biosynthesis
  • DNA-Binding Proteins / genetics*
  • Gene Expression Regulation* / physiology
  • Helix-Loop-Helix Motifs
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Hypoxia-Ischemia, Brain / etiology
  • Hypoxia-Ischemia, Brain / physiopathology*
  • In Situ Hybridization
  • Infarction, Middle Cerebral Artery / complications
  • Infarction, Middle Cerebral Artery / physiopathology
  • Male
  • Nuclear Proteins / biosynthesis
  • Nuclear Proteins / genetics*
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Transcription Factors / biosynthesis
  • Transcription Factors / genetics
  • Transcriptional Activation
  • Up-Regulation


  • DNA-Binding Proteins
  • Hif1a protein, rat
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Nuclear Proteins
  • RNA, Messenger
  • Transcription Factors