Brain genomic response following hypoxia and re-oxygenation in the neonatal rat. Identification of genes that might contribute to hypoxia-induced ischemic tolerance

J Biol Chem. 2002 Oct 18;277(42):39728-38. doi: 10.1074/jbc.M204619200. Epub 2002 Jul 26.


Hypoxic preconditioning (8% O2, 3 h) produces tolerance 24 h after hypoxic-ischemic brain injury in neonatal rats. To better understand the ischemic tolerance mechanisms induced by hypoxia, we used oligonucleotide microarrays to examine genomic responses in neonatal rat brain following 3 h of hypoxia (8% O2) and either 0, 6, 18, or 24 h of re-oxygenation. The results showed that hypoxia-inducible factor (HIF)-1- but not HIF-2-mediated gene expression may be involved in brain hypoxia-induced tolerance. Among the genes regulated by hypoxia, 12 genes were confirmed by real time reverse transcriptase-PCR as follows: VEGF, EPO, GLUT-1, adrenomedullin, propyl 4-hydroxylase alpha, MT-1, MKP-1, CELF, 12-lipoxygenase, t-PA, CAR-1, and an expressed sequence tag. Some genes, for example GLUT-1, MT-1, CELF, MKP-1, and t-PA did not show any hypoxic regulation in either astrocytes or neurons, suggesting that other cells are responsible for the up-regulation of these genes in the hypoxic brain. These genes were expressed in normal and hypoxic brain, heart, kidney, liver, and lung, with adrenomedullin, MT-1, and VEGF being prominently induced in brain by hypoxia. These results suggest that a number of endogenous molecular mechanisms may explain how hypoxic preconditioning protects against subsequent ischemia, and may provide novel therapeutic targets for treatment of cerebral ischemia.

Publication types

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

MeSH terms

  • Animals
  • Animals, Newborn
  • Blotting, Western
  • Brain / metabolism*
  • Brain / pathology
  • Expressed Sequence Tags
  • Female
  • Hypoxia*
  • Hypoxia-Ischemia, Brain / prevention & control
  • Ischemic Preconditioning
  • Male
  • Oligonucleotide Array Sequence Analysis
  • Oxygen / metabolism
  • RNA / metabolism
  • Rats
  • Reperfusion Injury / prevention & control
  • Reverse Transcriptase Polymerase Chain Reaction
  • Time Factors
  • Up-Regulation


  • RNA
  • Oxygen