title: Neuronal HIF-1α and HIF-2α deficiency improves neuronal survival and sensorimotor function in the early acute phase after ischemic stroke.
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.
authors.affiliation: Institute of Physiology and Pathophysiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Barteczek
authors.affiliation: Institute of Physiology and Pathophysiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Lexiao
authors.initials: L
authors.lastname: Li
authors.affiliation: Institute of Physiology and Pathophysiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Ernst
authors.affiliation: Institute of Physiology and Pathophysiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Laura-Inés
authors.initials: LI
authors.lastname: Böhler
authors.affiliation: Institute of Physiology and Pathophysiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Hugo H
authors.initials: HH
authors.lastname: Marti
authors.affiliation: Institute of Physiology and Pathophysiology, University of Heidelberg, Heidelberg, Germany reiner.kunze@physiologie.uni-heidelberg.de.
authors.forename: Reiner
authors.initials: R
authors.lastname: Kunze
mesh_terms: D000208:Acute Disease; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000172:deficiency* / Q000502:physiology; D002545:Brain Ischemia / Q000473:pathology*; D002470:Cell Survival; D005786:Gene Expression Regulation; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000172:deficiency* / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D066191:Sensorimotor Cortex / Q000502:physiology; D020521:Stroke / Q000473:pathology*; D013997:Time Factors; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human
keywords: Erythropoietin; hypoxia-inducible factor; ischemia; stroke; vascular endothelial growth factor