Induction of hypoxia‐inducible factor‐1 (HIF‐1) and its target genes following focal ischaemia in rat brain

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Abstract
HIF‐1 is a heterodimeric transcription factor, induced by hypoxia, that is composed of HIF‐1α and HIF‐1β 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‐1α, HIF‐1β and several HIF‐1 target genes in adult rat brain. After focal ischaemia, mRNAs encoding HIF‐1α, 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‐1α 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.