title: Roles of microRNA-1 in hypoxia-induced apoptotic insults to neuronal cells.
abstract: Hypoxia is a common occurrence in brain tumors and traumatic brain injury. microRNA (miR)-1 participates in the regulation of brain development and neuronal function. Interestingly, miR-1 can mediate ischemia-induced injury to cardiomyocytes. This study was designed to evaluate the roles of miR-1 in hypoxia-induced insults to neurons and the possible mechanisms. Exposure of neuro-2a cells to oxygen/glucose deprivation (OGD) or cobalt chloride decreased cell viability and induced cell apoptosis in time-dependent manners. In parallel, OGD caused augmentation of cellular Bax and cytochrome c levels, a reduction in the mitochondrial membrane potential (MMP), activation of caspase-3, and fragmentation of DNA. miR-1 was induced in neuro-2a cells by OGD. Knocking down miR-1 expression using specific antisense inhibitors significantly alleviated OGD-induced neuronal death. Administration of OGD to neuro-2a cells induced heat-shock protein (HSP)-70 messenger (m)RNA and protein expressions. A bioinformatic search revealed that miR-1-specific binding elements exist in the 3'-untranslated region of HSP-70 mRNA. Overexpression of miR-1 simultaneously attenuated OGD-induced HSP-70 mRNA and protein expressions. In comparison, knocking down miR-1 expression synergistically enhanced OGD-induced HSP-70 mRNA. As to the mechanism, reducing miR-1 expression lowered OGD-induced alterations in the MMP, caspase-3 activation, DNA fragmentation, and cell apoptosis. Taken together, this study shows that miR-1 can target HSP-70 expression and consequently mediate hypoxia-induced apoptotic insults to neuro-2a cells via an intrinsic Bax-mitochondrion-caspase protease pathway.
authors.affiliation: Department of Neurology, Chi-Mei Medical Center, Tainan, Taiwan.|Comprehensive Cancer Center, Taipei Medical University, Taipei, Taiwan.
authors.forename: Chia-Yu
authors.initials: CY
authors.lastname: Chang
authors.affiliation: Department of Neurosurgery, Wan-Fang Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Tai-Ngar
authors.initials: TN
authors.lastname: Lui
authors.affiliation: Comprehensive Cancer Center, Taipei Medical University, Taipei, Taiwan.
authors.forename: Jia-Wei
authors.initials: JW
authors.lastname: Lin
authors.affiliation: Brain Disease Research Center and Department of Anesthesiology, Wan-Fang Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yi-Ling
authors.initials: YL
authors.lastname: Lin
authors.affiliation: Department of Anesthesiology, Chi-Mei Medical Center, Tainan, Taiwan.
authors.forename: Chung-Hsi
authors.initials: CH
authors.lastname: Hsing
authors.affiliation: Department of Anesthesiology, Chi-Mei Medical Center, Tainan, Taiwan.
authors.forename: Jhi-Joung
authors.initials: JJ
authors.lastname: Wang
authors.affiliation: Comprehensive Cancer Center, Taipei Medical University, Taipei, Taiwan. rmchen@tmu.edu.tw.|Graduate Institute of Medical Sciences, Taipei Medical University, 250 Wu-Xing St., Taipei, 110, Taiwan. rmchen@tmu.edu.tw.|Brain Disease Research Center and Department of Anesthesiology, Wan-Fang Hospital, Taipei Medical University, Taipei, Taiwan. rmchen@tmu.edu.tw.|Anesthetics and Toxicology Research Center, Taipei Medical University Hospital, Taipei, Taiwan. rmchen@tmu.edu.tw.
authors.forename: Ruei-Ming
authors.initials: RM
authors.lastname: Chen
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002470:Cell Survival; D003035:Cobalt / Q000633:toxicity; D053938:DNA Fragmentation; D005786:Gene Expression Regulation; D005947:Glucose / Q000172:deficiency; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010100:Oxygen / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection
chemical_list: D051017:Apoptosis Regulatory Proteins; D018840:HSP70 Heat-Shock Proteins; D035683:MicroRNAs; C517731:Mirn1 microRNA, mouse; D003035:Cobalt; C018021:cobaltous chloride; D005947:Glucose; D010100:Oxygen
keywords: HSP-70; Hypoxia; Intrinsic mechanism; Neural apoptosis; miR-1