title: Neuron-specific inactivation of the hypoxia inducible factor 1 alpha increases brain injury in a mouse model of transient focal cerebral ischemia.
abstract: In the present study, we show a biphasic activation of hypoxia inducible factor 1alpha (HIF-1) after stroke that lasts for up to 10 d, suggesting the involvement of the HIF pathway in several aspects of the pathophysiology of cerebral ischemia. We provide evidence that HIF-1-mediated responses have an overall beneficial role in the ischemic brain as indicated by increased tissue damage and reduced survival rate of mice with neuron-specific knockdown of HIF-1alpha that were subjected to transient focal cerebral ischemia. In addition, we demonstrated that drugs known to activate HIF-1 in cultured cells as well as in vivo had neuroprotective properties in this model of cerebral ischemia. This protective effect was significantly attenuated but not completely abolished in neuron-specific HIF-1alpha-deficient mice, suggesting that alternative mechanisms of neuroprotection are also implicated. Last, our study showed that hypoxia-induced tolerance to ischemia was preserved in neuron-specific HIF-1alpha-deficient mice, indicating that the neuroprotective effects of hypoxic preconditioning do not depend on neuronal HIF-1 activation.
authors.affiliation: Burke Medical Research Institute, White Plains, New York 10605, USA.
authors.forename: Oxana
authors.initials: O
authors.lastname: Baranova
authors.forename: Luis F
authors.initials: LF
authors.lastname: Miranda
authors.forename: Paola
authors.initials: P
authors.lastname: Pichiule
authors.forename: Ioannis
authors.initials: I
authors.lastname: Dragatsis
authors.forename: Randall S
authors.initials: RS
authors.lastname: Johnson
authors.forename: Juan C
authors.initials: JC
authors.lastname: Chavez
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000235:genetics / Q000378:metabolism*; D002560:Cerebrovascular Circulation / Q000502:physiology; D004195:Disease Models, Animal; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics; D002546:Ischemic Attack, Transient / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009474:Neurons / Q000378:metabolism*
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit