Induction of hypoxia-inducible factor-1 (HIF-1) and its target genes following focal ischaemia in rat brain.
HIF-1 is a heterodimeric transcription factor, induced by hypoxia, that is composed of HIF-1alpha and HIF-1beta protein subunits. It binds to promoter/enhancer elements and stimulates the transcription of hypoxia-inducible target genes, including glucose transporter-1 and the glycolytic enzymes. Because HIF-1 activation might promote cell survival in hypoxic tissues, we studied the effect of permanent middle cerebral artery occlusion on the expression of HIF-1alpha, HIF-1beta and several HIF-1 target genes in adult rat brain. After focal ischaemia, mRNAs encoding HIF-1alpha, glucose transporter-1 and several glycolytic enzymes were up-regulated in the peri-infarct penumbra. This was observed by 7.5 h after the onset of ischaemia and increased further at 19 and 24 h. Regional cerebral blood flow was moderately decreased at 1 and 24 h after the ischaemia in areas of HIF-1 and HIF-1 target gene induction. Because hypoxia induces HIF-1 in other tissues, systemic hypoxia (6% O2 for 4.5 h) was also shown to increase HIF-1alpha protein expression in the adult rat brain. It is proposed that decreased blood flow to the penumbra decreases the supply of oxygen and that this induces HIF-1 and its target genes. This is the first study to show induction of HIF-1 after focal ischaemia in brain. Increased expression of HIF-1 target genes as a result of HIF-1 activation by hypoxia may contribute to tissue viability in the hypoxic/ischaemic penumbra by increasing glucose transport and glycolysis.
Bergeron
M
M
Department of Neurology, University of California at San Francisco and Veterans Affairs Medical Center, California 94121, USA.
Yu
A Y
AY
Solway
K E
KE
Semenza
G L
GL
Sharp
F R
FR
D000818:Animals; D001921:Brain / Q000378:metabolism*; D002560:Cerebrovascular Circulation / Q000502:physiology; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D005786:Gene Expression Regulation / Q000502:physiology; D018257:Helix-Loop-Helix Motifs; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D020925:Hypoxia-Ischemia, Brain / Q000209:etiology / Q000503:physiopathology*; D017403:In Situ Hybridization; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000503:physiopathology; D008297:Male; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D015533:Transcriptional Activation; D015854:Up-Regulation
D004268:DNA-Binding Proteins; C497444:Hif1a protein, rat; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D012333:RNA, Messenger; D014157:Transcription Factors