title: Hypoxia-independent mechanisms of HIF-1α expression in astrocytes after ischemic preconditioning.
abstract: We recently demonstrated that ischemic tolerance was dependent on astrocytes, for which HIF-1α had an essential role. The mild ischemia (preconditioning; PC) increased HIF-1α in a biphasic pattern, that is, a quick and transient increase in neurons, followed by a slow and sustained increase in astrocytes. However, mechanisms underlying such temporal difference in HIF-1α increase remain totally unknown. Here, we show that unlike a hypoxia-dependent mechanism in neurons, astrocytes increase HIF-1α via a novel hypoxia-independent but P2X7-dependent mechanism. Using a middle cerebral artery occlusion (MCAO) model of mice, we found that the PC (a 15-min MCAO period)-evoked increase in HIF-1α in neurons was quick and transient (from 1 to 3 days after PC), but that in astrocytes was slow-onset and long-lasting (from 3 days to at least 2 weeks after PC). The neuronal HIF-1α increase was dependent on inhibition of PHD2, an oxygen-dependent HIF-1α degrading enzyme, whereas astrocytic one was independent of PHD2. Astrocytes even do not possess this enzyme. Instead, they produced a sustained increase in P2X7 receptors, activation of which resulted in HIF-1α increase. The hypoxia-independent but P2X7-receptor-dependent mechanism could allow astrocytes to cause long-lasting HIF-1α expression, thereby leading to induction of ischemic tolerance efficiently. GLIA 2017;65:523-530.
authors.affiliation: Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Chuo, Yamanashi, 409-3898, Japan.|Department of Liaison Academy, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, 409-3898, Japan.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Hirayama
authors.affiliation: Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Chuo, Yamanashi, 409-3898, Japan.
authors.forename: Schuichi
authors.initials: S
authors.lastname: Koizumi
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D001921:Brain / Q000473:pathology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D007839:Functional Laterality / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D000860:Hypoxia / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology*; D019194:Ischemic Preconditioning / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D058486:Receptors, Purinergic P2X7 / Q000172:deficiency / Q000235:genetics
chemical_list: D005904:Glial Fibrillary Acidic Protein; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010975:Platelet Aggregation Inhibitors; D058486:Receptors, Purinergic P2X7; C033901:3'-O-(4-benzoyl)benzoyladenosine 5'-triphosphate; D000255:Adenosine Triphosphate; D010751:Phosphopyruvate Hydratase
keywords: HIF-1α; P2X7 receptor; PHD2; astrocytes; ischemic tolerance