Hypoxic preconditioning protects against ischemic brain injury - PubMed (original) (raw)

Review

Hypoxic preconditioning protects against ischemic brain injury

Frank R Sharp et al. NeuroRx. 2004 Jan.

Abstract

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.

PubMed Disclaimer

Figures

FIG. 1.

Hypoxia and growth factor stabilization of HIF-1α leads to binding to HIF-1β and binding to HREs in promoters of HIF target genes to activate transcription of HIF target genes.

FIG. 2.

Normoxia leads to activation of HIF proline hydroxylase, which hydroxylates two prolines on HIF-1α (prolines 402 and 564) that leads to binding of pVHL and elongin-C,-B, Rbx, and Cul2 and degradation of HIF-1α in the proteasome.

FIG. 3.

Normoxia leads to activation of HIF asparagine hydroxylase, which hydroxylates asparagine 803 on HIF-1α that prevents binding of p300 to the HIF-1α and HIF-1β complex and impairs activation of HIF target genes.

References

1. Hawaleshka A, Jacobsohn E. Ischaemic preconditioning: mechanisms and potential clinical applications. Can J Anaesth 45: 670–682, 1998. -PubMed
1. Zhu Y, Ohlemiller KK, McMahan BK, Gidday JM. Mouse models of retinal ischemic tolerance. Invest Ophthalmol Vis Sci 43: 1903–1911, 2002. -PubMed
1. Zimmermann C, Ginis I, Furuya K, Klimanis D, Ruetzler C, Spatz M, Hallenbeck JM. Lipopolysaccharide-induced ischemic tolerance is associated with increased levels of ceramide in brain and in plasma. Brain Res 895: 59–65, 2001. -PubMed
1. Barone FC, White RF, Spera PA, Ellison J, Currie RW, Wang X, Feuerstein GZ. Ischemic preconditioning and brain tolerance: temporal histological and functional outcomes, protein synthesis requirement, and interleukin-1 receptor antagonist and early gene expression. Stroke 29: 1937–1950, 1998. -PubMed
1. Blondeau N, Widmann C, Lazdunski M, Heurteaux C. Activation of the nuclear factor-κB is a key event in brain tolerance. J Neurosci 21: 4668–4677, 2001. -PMC -PubMed

Hypoxic preconditioning protects against ischemic brain injury - PubMed (original) (raw)