Hypoxia-inducible factor in brain

Frank R Sharp, Marcelle Bergeron, Myriam Bernaudin

Research output: Contribution to journalArticle

88 Scopus citations

Abstract

HIF-1 is composed of HIF-1α and HIF-1β protein subunits. HIF-1 is induced by hypoxia and binds to promoter / enhancer elements and stimulates the transcription of hypoxia-inducible target genes. Because HIF-1 activation might promote cell survival in hypoxic tissues, we studied the effect of stroke on the expression of HIF-1α, HIF-1β and several HIF-1 target genes in adult rat brain. After focal cerebral ischemia, mRNAs encoding HIF-1α, glucose transporter-1 and several glycolytic enzymes including lactate dehydrogenase were up-regulated in the areas around the infarction. HIF and its target genes were induced by 7.5 hours after the onset of ischemia and increased further at 19 and 24 hours. Since hypoxia induces HIF in other tissues, systemic hypoxia (6% O2 for 4.5h) 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. Because HIF-1 activation may promote cell survival in hypoxic tissues, we studied the effect of hypoxic preconditioning on HIF-1 expression in neonatal rat brain. Hypoxic preconditioning (8% O2/3hrs), a treatment known to protect the newborn rat brain against hypoxic-ischemic injury, markedly increased HIF-1α and HIF-1β expression. We also studied the effect of two other known HIF-1 inducers, cobalt chloride (CoCl2) and desferrioxamine (DFX), on HIF-1 expression and neuroprotection in newborn brain. HIF-1α and HIF-1β protein levels were markedly increased after i.p. injection of CoCl2 and DFX. Preconditioning with CoCl2 or DFX 24 hours before the stroke decreased infarction by 75% and 56% respectively, compared with vehicle-injected, littermate controls. Thus, HIF-1 activation could contribute to protective brain preconditioning.

Original languageEnglish (US)
Pages (from-to)273-291
Number of pages19
JournalAdvances in Experimental Medicine and Biology
Volume502
StatePublished - 2001
Externally publishedYes

Keywords

  • ARNT
  • Cerebral ischemia
  • Hypoxia
  • Hypoxia-inducible factor
  • Ischemic tolerance
  • Lactate dehydrogenase
  • Pre-conditioning
  • Stroke

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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