Journal
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
Volume 37, Issue 1, Pages 291-306Publisher
SAGE PUBLICATIONS INC
DOI: 10.1177/0271678X15624933
Keywords
Erythropoietin; hypoxia-inducible factor; ischemia; stroke; vascular endothelial growth factor
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Funding
- Else Kroner-Fresenius-Stiftung [2012_A171]
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Hypoxia-inducible factors mediate adaptive responses to ischemia, among others, by induction of anti- and pro-survival genes. Thus, the impact of HIF on neuronal survival upon stroke is controversial. Therefore, neuron-specific knockout mice deficient for Hif1 alpha and Hif2 alpha were exposed to inspiratory hypoxia or ischemia-reperfusion injury. Both Hif1 alpha- and Hif2 alpha-deficient mice showed no altered infarct and edema size, suggesting that both HIF-alpha subunits might compensate for each other. Accordingly, hypoxic HIF-target gene regulation was marginally affected with exception of anti-survival Bnip3 and pro-survival erythropoietin. In the early acute stage upon stroke, Hif1 alpha/Hif2 alpha double knockout mice exhibited significantly reduced expression of the anti-survival Bnip3, Bnip3L, and Pmaip1. Accordingly, global cell death and edema were significantly reduced upon 24 h but not 72 h reperfusion. Behavioral assessment indicated that Hif1 alpha/Hif2 alpha-deficient mice initially performed better, but became significantly more impaired after 72 h accompanied by increased apoptosis and reduced angiogenesis. Our findings suggest that in neurons HIF-1 and HIF-2 have redundant functions for cellular survival under ischemic conditions. By contrast, lack of anti-survival factors in Hif1 alpha/Hif2 alpha-deficient mice might protect from early acute neuronal cell death and neurological impairment, indicating a benefit of HIF-pathway inhibition in neurons in the very acute phase after ischemic stroke.
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