Brain-Specific Knock-Out of Hypoxia-Inducible Factor-1α Reduces Rather Than Increases Hypoxic-Ischemic Damage

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Abstract
Hypoxia-inducible factor-1α (HIF-1α) plays an essential role in cellular and systemic O2homeostasis by regulating the expression of genes important in glycolysis, erythropoiesis, angiogenesis, and catecholamine metabolism. It is also believed to be a key component of the cellular response to hypoxia and ischemia under pathophysiological conditions, such as stroke. To clarify the function of HIF-1α in the brain, we exposed adult mice with late-stage brain deletion of HIF-1α to hypoxic injuries. Contrary to expectations, the brains from theHIF-1α-deficient mice were protected from hypoxia-induced cell death. These surprising findings suggest that decreasing the level of HIF-1α can be neuroprotective. Gene chip expression analysis revealed that, contrary to expectations, the majority of hypoxia-dependent gene-expression changes were unaltered, whereas a specific downregulation of apoptotic genes was observed in theHIF-1α-deficient mice. Although the role of HIF-1α has been extensively characterizedin vitro, in cancer models, and in chronic preconditioning paradigms, this is the first study to evaluate the role of HIF-1αin vivoin the brain in response to acute hypoxia/ischemia. Our data suggest, that in acute hypoxia, the neuroprotection found in theHIF-1α-deficient mice is mechanistically consistent with a predominant role of HIF-1α as proapoptotic and loss of function leads to neuroprotection. Furthermore, our data suggest that functional redundancy develops after excluding HIF-1α, leading to the preservation of gene expression regulating the majority of other previously characterized HIF-dependent genes.