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The Journal of Neuroscience, April 20, 2005, 25(16):4099-4107; doi:10.1523/JNEUROSCI.4555-04.2005

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

Rob Helton,^1 * Jiankun Cui,^2 * John R. Scheel,^1 * Julie A. Ellison,¹ Chris Ames,¹ Claire Gibson,² Barbara Blouw,³ Ling Ouyang,¹ Ioannis Dragatsis,⁴ Scott Zeitlin,⁵ Randall S. Johnson,³ Stuart A. Lipton,² and Carrolee Barlow¹

¹Laboratory of Genetics, The Salk Institute for Biological Studies, and ²Center for Neuroscience and Aging, The Burnham Institute, La Jolla, California 92037, ³Molecular Biology Section, Division of Biology, University of California, San Diego, La Jolla, California 92093, ⁴Department of Physiology, The University of Tennessee, Health Science Center, Memphis, Tennessee 38163, and ⁵Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, Virginia 22908

Hypoxia-inducible factor-1 (HIF-1) 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-1 in the brain, we exposed adult mice with late-stage brain deletion of HIF-1 to hypoxic injuries. Contrary to expectations, the brains from the HIF-1-deficient mice were protected from hypoxia-induced cell death. These surprising findings suggest that decreasing the level of HIF-1 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-1-deficient mice. Although the role of HIF-1 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-1 in vivo in the brain in response to acute hypoxia/ischemia. Our data suggest, that in acute hypoxia, the neuroprotection found in the HIF-1-deficient mice is mechanistically consistent with a predominant role of HIF-1 as proapoptotic and loss of function leads to neuroprotection. Furthermore, our data suggest that functional redundancy develops after excluding HIF-1, leading to the preservation of gene expression regulating the majority of other previously characterized HIF-dependent genes.

Key words: apoptosis; carotid; hippocampus; hypoxia; neuron; transcription

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Received Nov 5, 2004; revised February 17, 2005; accepted February 18, 2005.

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