Role of hypoxia-inducible factor-1 in hypoxia-induced ischemic tolerance in neonatal rat brain.
Hypoxia-inducible factor-1 (HIF-1) is a heterodimer composed of HIF-1alpha and HIF-1beta protein subunits. This transcription factor is essential for the activation of hypoxia-inducible genes like erythropoietin, some glucose transporters, the glycolytic enzymes, and vascular endothelial growth factor. 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 for 3 hours), a treatment known to protect the newborn rat brain against hypoxic-ischemic injury, markedly increased HIF-1alpha and HIF-1beta expression. To support the role of HIF-1 in protective preconditioning, 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-1alpha and HIF-1beta protein levels were markedly increased after intraperitoneal injection of CoCl2 (60 mg/kg) and moderately increased after intraperitoneal injection of DFX (200 mg/kg) 1 to 3 hours after the injections. Preconditioning with CoCl2 or DFX 24 hours before hypoxia-ischemia afforded 75 and 56% brain protection, respectively, compared with that in vehicle-injected littermate controls. Thus, HIF-1 activation could contribute to protective brain preconditioning, which could be used in high-risk deliveries and other clinical situations.
Bergeron
M
M
Department of Neurology, University of Cincinnati, OH 45267-0536, USA.
Gidday
J M
JM
Yu
A Y
AY
Semenza
G L
GL
Ferriero
D M
DM
Sharp
F R
FR
D000818:Animals; D015153:Blotting, Western; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D009687:Nuclear Proteins / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors
D004268:DNA-Binding Proteins; C497444:Hif1a protein, rat; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D014157:Transcription Factors