title: HIF-1α is neuroprotective during the early phases of mild hypoxia in rat cortical neurons.
abstract: Hypoxia-inducible factor 1α (HIF-1α) is a transcription factor that plays a key role in regulating the adaptive response to hypoxia. HIF-1α is stabilised during hypoxia and, after dimerisation with hypoxia-inducible factor 1β (HIF-1β), triggers the expression of various genes involved in cell cycle control and energy metabolism associated with cell survival. However, HIF-1α also regulates the expression of proapoptotic genes. The aim of this study was to ascertain the influence of HIF-1α on neurotoxicity evoked by hypoxia in rat cortical neurons. We found that mild hypoxia induces time-dependent neuronal death involving free radical production, mitochondrial depolarisation, cytochrome c release and caspase-3 activation. Lentivirus-mediated HIF-1α knockdown markedly strengthened all of these effects during the initial 24h of hypoxia, which suggests that HIF-1α plays a neuroprotective role in hypoxia-mediated neuronal death. After this initial period, the protective actions of HIF-1α disappeared over the course of the hypoxia-mediated HIF-1α stabilisation. Moreover, lentiviral-mediated overexpression of HIF-1α increased lactate dehydrogenase (LDH) A, one of the target genes for HIF-1α, but did not show protective actions on hypoxia-mediated neuronal death, indicating that the level of endogenous HIF-1α stabilisation achieved during hypoxia was already the maximum required for HIF-1α transcription activities. These results indicate that HIF-1α is neuroprotective in the early phases of hypoxia.
authors.affiliation: Unidad Asociada Neurodeath, Facultad de Medicina, Universidad de Castilla-La Mancha, 02071 Albacete, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: López-Hernández
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Posadas
authors.forename: Petar
authors.initials: P
authors.lastname: Podlesniy
authors.forename: María A
authors.initials: MA
authors.lastname: Abad
authors.forename: Ramón
authors.initials: R
authors.lastname: Trullas
authors.forename: Valentín
authors.initials: V
authors.lastname: Ceña
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D016923:Cell Death; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D051545:Cyclooxygenase 1 / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D016166:Free Radical Scavengers / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D005978:Glutathione / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics; D000860:Hypoxia / Q000378:metabolism / Q000473:pathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D008565:Membrane Proteins / Q000378:metabolism; D008665:Metalloporphyrins / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000648:ultrastructure; D010100:Oxygen / Q000378:metabolism; D010617:Phenanthridines; D034622:RNA Interference / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species; D013778:Tetrazolium Salts; D013844:Thiazoles; D013997:Time Factors
chemical_list: C521281:5-(6'-triphenylphosphoniumhexyl)-5,6-dihydro-6-phenyl-3,8-phenanthridinediammine; D016166:Free Radical Scavengers; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008565:Membrane Proteins; D008665:Metalloporphyrins; D010617:Phenanthridines; D017382:Reactive Oxygen Species; D013778:Tetrazolium Salts; D013844:Thiazoles; C097284:manganese(III)-tetrakis(4-benzoic acid)porphyrin; D049452:Green Fluorescent Proteins; D045304:Cytochromes c; D007770:L-Lactate Dehydrogenase; D051545:Cyclooxygenase 1; C496513:Ptgs1 protein, rat; C022616:thiazolyl blue; D005978:Glutathione; D010100:Oxygen