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