Brain-Specific Knock-Out of Hypoxia-Inducible Factor-1Α
The Journal of Neuroscience, April 20, 2005 • 25(16):4099–4107 • 4099 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 decreas- ing 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.
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