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

Marcelle Bergeron, Aimee Y. Yu, Karen E. Solway, Gregg L. Semenza, Frank R Sharp

Research output: Contribution to journalArticlepeer-review

346 Scopus citations

Abstract

HIF-1 is a heterodimeric transcription factor, induced by hypoxia, that is composed of HIF-1α and HIF-1β 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-1α, HIF-1β and several HIF-1 target genes in adult rat brain. After focal ischaemia, mRNAs encoding HIF-1α, 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-1α 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.

Original languageEnglish (US)
Pages (from-to)4159-4170
Number of pages12
JournalEuropean Journal of Neuroscience
Volume11
Issue number12
DOIs
StatePublished - Dec 1999

Keywords

  • Glucose transporter
  • Glycolysis
  • Hypoxia
  • Penumbra
  • Transcription factor

ASJC Scopus subject areas

  • Neuroscience(all)

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