Hypoxic preconditioning induces changes in HIF-1 target genes in neonatal rat brain.
Hypoxic preconditioning induces tolerance to hypoxic-ischemic injury in neonatal rat brain and is associated with changes in gene expression. Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that is strongly induced by hypoxia or the hypoxia-mimetic compound cobalt chloride (CoCl(2)). Hypoxia-inducible factor-1 modulates the expression of several target genes including the glycolytic enzymes, glucose transporter-1 (GLUT-1), and erythropoietin. Recently, HIF-1 expression was shown to increase after hypoxic and CoCl(2) preconditioning in newborn rat brain. To study the involvement of HIF-1 target genes in neonatal hypoxia-induced ischemic tolerance, the authors examined the brains of newborn rats after exposure to hypoxia (8% O(2) for 3 hours) or injection of CoCl(2) (60 mg/kg). Preconditioning with hypoxia or CoCl(2) 24 hours before hypoxia-ischemia afforded a 96% and 76% brain protection, respectively, compared with littermate control animals. Hypoxic preconditioning increased the expression of GLUT-1 mRNA and protein, and of aldolase, phosphofructokinase, and lactate dehydrogenase proteins but not mRNA. This suggests that the modulation of glucose transport and glycolysis by hypoxia may contribute to the development of hypoxia-induced tolerance. In contrast, preconditioning with CoCl(2) did not produce any change in HIF-1 target gene expression suggesting that different molecular mechanisms may be involved in the induction of tolerance by hypoxia and CoCl(2) in newborn brain.
Jones
N M
NM
Neuroscience Division, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA.
Bergeron
M
M
D000818:Animals; D000831:Animals, Newborn; D015152:Blotting, Northern; D001921:Brain / Q000098:blood supply / Q000378:metabolism*; D003035:Cobalt / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics*; D004921:Erythropoietin / Q000235:genetics; D005260:Female; D005634:Fructose-Bisphosphate Aldolase / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D051272:Glucose Transporter Type 1; D006019:Glycolysis / Q000502:physiology; D002534:Hypoxia, Brain / Q000503:physiopathology*; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019194:Ischemic Preconditioning; D007770:L-Lactate Dehydrogenase / Q000235:genetics; D008297:Male; D009004:Monosaccharide Transport Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics*; D010732:Phosphofructokinase-1 / Q000235:genetics; D011770:Pyruvate Kinase / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors
D004268:DNA-Binding Proteins; D051272:Glucose Transporter Type 1; C497444:Hif1a protein, rat; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009004:Monosaccharide Transport Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; C495679:Slc2a1 protein, rat; D014157:Transcription Factors; D004921:Erythropoietin; D003035:Cobalt; D007770:L-Lactate Dehydrogenase; D010732:Phosphofructokinase-1; D011770:Pyruvate Kinase; D005634:Fructose-Bisphosphate Aldolase; C018021:cobaltous chloride