Hypoxic preconditioning protects against ischemic brain injury.
Animals exposed to brief periods of moderate hypoxia (8% to 10% oxygen for 3 hours) are protected against cerebral and cardiac ischemia between 1 and 2 days later. This hypoxia preconditioning requires new RNA and protein synthesis. The mechanism of this hypoxia-induced tolerance correlates with the induction of the hypoxia-inducible factor (HIF), a transcription factor heterodimeric complex composed of inducible HIF-1alpha and constitutive HIF-1beta proteins that bind to the hypoxia response elements in a number of HIF target genes. Our recent studies show that HIF-1alpha correlates with hypoxia induced tolerance in neonatal rat brain. HIF target genes, also induced following hypoxia-induced tolerance, include vascular endothelial growth factor, erythropoietin, glucose transporters, glycolytic enzymes, and many other genes. Some or all of these genes may contribute to hypoxia-induced protection against ischemia. HIF induction of the glycolytic enzymes accounts in part for the Pasteur effect in brain and other tissues. Hypoxia-induced tolerance is not likely to be equivalent to treatment with a single HIF target gene protein since other transcription factors including Egr-1 (NGFI-A) have been implicated in hypoxia regulation of gene expression. Understanding the mechanisms and genes involved in hypoxic tolerance may provide new therapeutic targets to treat ischemic injury and enhance recovery.
Sharp
Frank R
FR
Department of Neurology, University of Cincinnati, Ohio 45267, USA. frank.sharp@uc.edu
Ran
Ruiqiong
R
Lu
Aigang
A
Tang
Yang
Y
Strauss
Kenneth I
KI
Glass
Todd
T
Ardizzone
Tim
T
Bernaudin
Myriam
M
D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002545:Brain Ischemia / Q000235:genetics / Q000503:physiopathology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D015870:Gene Expression; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019194:Ischemic Preconditioning; D051381:Rats; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
C497398:ARNT protein, rat; D004268:DNA-Binding Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018336:Receptors, Aryl Hydrocarbon; D014157:Transcription Factors; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator
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