Neuronal HIF-1α and HIF-2α deficiency improves neuronal survival and sensorimotor function in the early acute phase after ischemic stroke

Once again this will not be followed up with human clinical trials. But since we have NO stroke strategy or stroke leadership in any part of stroke this will fall thru the cracks. Our fucking failures of stroke associations once again will lead the way to failure but not doing anything about this.
http://jcb.sagepub.com/content/early/2016/01/08/0271678X15624933.abstract?

1. Philipp Barteczek
2. Lexiao Li
3. Anne-Sophie Ernst
4. Laura-Inés Böhler
5. Hugo H Marti
6. Reiner Kunze⇑

1. Institute of Physiology and Pathophysiology, University of Heidelberg, Heidelberg, Germany

1. 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.