HIF-1¦Á is neuroprotective during the early phases of mild hypoxia in rat cortical neurons

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• 作者：Beatriz Ló ; pez-Herná ; ndez^a ; ^b ; Inmaculada Posadas^a ; ^b ; Petar Podlesniy^b ; ^c ; Marí ; a A. Abad^b ; ^c ; Ramó ; n Trullas^b ; ^c ; Valentí ; n Ceñ ; a^a ; ^b ; ^{valentin.cena@gmail.com}
• 关键词：¦·m ; mitochondrial transmembrane potential ; BCA ; bicinchoninic acid ; DIV ; days in vitro ; DTT ; dithiothreitol ; EGTA ; ethylene glycol-bis (¦Â-aminoethyl ether)-N ; N ; N&prime ; N&prime ; -tetraacetic acid ; FCCP ; carbonyl cyanide p-trifluoromethoxyphenylhydrazone
• 刊名：Experimental Neurology
• 出版年：2012
• 出版时间：January 2012
• 年：2012
• 卷：233
• 期：1
• 页码：543-554
• 全文大小：1140 K

文摘

Hypoxia-inducible factor 1¦Á (HIF-1¦Á) is a transcription factor that plays a key role in regulating the adaptive response to hypoxia. HIF-1¦Á is stabilised during hypoxia and, after dimerisation with hypoxia-inducible factor 1¦Â (HIF-1¦Â), triggers the expression of various genes involved in cell cycle control and energy metabolism associated with cell survival. However, HIF-1¦Á also regulates the expression of proapoptotic genes. The aim of this study was to ascertain the influence of HIF-1¦Á 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-1¦Á knockdown markedly strengthened all of these effects during the initial 24 h of hypoxia, which suggests that HIF-1¦Á plays a neuroprotective role in hypoxia-mediated neuronal death. After this initial period, the protective actions of HIF-1¦Á disappeared over the course of the hypoxia-mediated HIF-1¦Á stabilisation. Moreover, lentiviral-mediated overexpression of HIF-1¦Á increased lactate dehydrogenase (LDH) A, one of the target genes for HIF-1¦Á, but did not show protective actions on hypoxia-mediated neuronal death, indicating that the level of endogenous HIF-1¦Á stabilisation achieved during hypoxia was already the maximum required for HIF-1¦Á transcription activities. These results indicate that HIF-1¦Á is neuroprotective in the early phases of hypoxia.