Brain-specific knock-out of hypoxia-inducible factor-1alpha reduces rather than increases hypoxic-ischemic damage.
Hypoxia-inducible factor-1alpha (HIF-1alpha) plays an essential role in cellular and systemic O(2) 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-1alpha in the brain, we exposed adult mice with late-stage brain deletion of HIF-1alpha to hypoxic injuries. Contrary to expectations, the brains from the HIF-1alpha-deficient mice were protected from hypoxia-induced cell death. These surprising findings suggest that decreasing the level of HIF-1alpha 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-1alpha-deficient mice. Although the role of HIF-1alpha 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-1alpha in vivo in the brain in response to acute hypoxia/ischemia. Our data suggest, that in acute hypoxia, the neuroprotection found in the HIF-1alpha-deficient mice is mechanistically consistent with a predominant role of HIF-1alpha as proapoptotic and loss of function leads to neuroprotection. Furthermore, our data suggest that functional redundancy develops after excluding HIF-1alpha, leading to the preservation of gene expression regulating the majority of other previously characterized HIF-dependent genes.
Helton
Rob
R
Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
Cui
Jiankun
J
Scheel
John R
JR
Ellison
Julie A
JA
Ames
Chris
C
Gibson
Claire
C
Blouw
Barbara
B
Ouyang
Ling
L
Dragatsis
Ioannis
I
Zeitlin
Scott
S
Johnson
Randall S
RS
Lipton
Stuart A
SA
Barlow
Carrolee
C
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D015139:Blotting, Southern / Q000379:methods; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D002452:Cell Count / Q000379:methods; D017362:Cyclic AMP Response Element-Binding Protein / Q000172:deficiency; D005455:Fluorescent Antibody Technique / Q000379:methods; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000502:physiology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000172:deficiency* / Q000502:physiology*; D020925:Hypoxia-Ischemia, Brain / Q000235:genetics / Q000378:metabolism*; D020287:In Situ Nick-End Labeling / Q000379:methods; D051379:Mice; D018345:Mice, Knockout; D046228:Microarray Analysis / Q000379:methods; D008954:Models, Biological; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency
D017362:Cyclic AMP Response Element-Binding Protein; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017346:Protein Serine-Threonine Kinases; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase