http://jcb.sagepub.com/content/early/2016/01/08/0271678X15624933.abstract?
- Reiner Kunze, Institute of Physiology and Pathophysiology, University of Heidelberg, Im Neuenheimer Feld 326, Heidelberg 69120, Germany. Email: reiner.kunze@physiologie.uni-heidelberg.de
Abstract
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 Hif1a and Hif2a were exposed to inspiratory hypoxia or ischemia–reperfusion injury. Both Hif1a- and Hif2a-deficient mice showed no altered infarct and edema size, suggesting that both HIF-α 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, Hif1a/Hif2a 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 Hif1a/Hif2a-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 Hif1a/Hif2a-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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