PT  - JOURNAL ARTICLE
AU  - Rob Helton
AU  - Jiankun Cui
AU  - John R. Scheel
AU  - Julie A. Ellison
AU  - Chris Ames
AU  - Claire Gibson
AU  - Barbara Blouw
AU  - Ling Ouyang
AU  - Ioannis Dragatsis
AU  - Scott Zeitlin
AU  - Randall S. Johnson
AU  - Stuart A. Lipton
AU  - Carrolee Barlow
TI  - Brain-Specific Knock-Out of Hypoxia-Inducible Factor-1α Reduces Rather Than Increases Hypoxic-Ischemic Damage
AID  - 10.1523/JNEUROSCI.4555-04.2005
DP  - 2005 Apr 20
TA  - The Journal of Neuroscience
PG  - 4099--4107
VI  - 25
IP  - 16
4099  - http://www.jneurosci.org/content/25/16/4099.short
4100  - http://www.jneurosci.org/content/25/16/4099.full
SO  - J. Neurosci.2005 Apr 20; 25
AB  - Hypoxia-inducible factor-1α (HIF-1α) plays an essential role in cellular and systemic O2 homeostasis 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 the HIF-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 the HIF-1α-deficient mice. Although the role of HIF-1α has been extensively characterized in vitro, in cancer models, and in chronic preconditioning paradigms, this is the first study to evaluate the role of HIF-1α in vivo in the brain in response to acute hypoxia/ischemia. Our data suggest, that in acute hypoxia, the neuroprotection found in the HIF-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.