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Roles of microRNA-1 in hypoxia-induced apoptotic insults to neuronal cells

  • Organ Toxicity and Mechanisms
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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.

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Acknowledgments

This project was supported by grants from the Chi-Mei Medical Center (100CM-TMU-13-3), Tainan, Taiwan; Wan-Fang Hospital (101wf-eva-06), the National Science Council (NSC101-2314-B-038-008-MY3; NSC101-2314-B-038-003-MY3), and Health and Welfare Surcharge of Tobacco Products (MOHW103-TD-B-111-01), Taipei, Taiwan.

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Authors and Affiliations

  1. Department of Neurology, Chi-Mei Medical Center, Tainan, Taiwan

    Chia-Yu Chang

  2. Department of Anesthesiology, Chi-Mei Medical Center, Tainan, Taiwan

    Chung-Hsi Hsing & Jhi-Joung Wang

  3. Comprehensive Cancer Center, Taipei Medical University, Taipei, Taiwan

    Chia-Yu Chang, Jia-Wei Lin & Ruei-Ming Chen

  4. Graduate Institute of Medical Sciences, Taipei Medical University, 250 Wu-Xing St., Taipei, 110, Taiwan

    Ruei-Ming Chen

  5. Brain Disease Research Center and Department of Anesthesiology, Wan-Fang Hospital, Taipei Medical University, Taipei, Taiwan

    Yi-Ling Lin & Ruei-Ming Chen

  6. Department of Neurosurgery, Wan-Fang Hospital, Taipei Medical University, Taipei, Taiwan

    Tai-Ngar Lui

  7. Anesthetics and Toxicology Research Center, Taipei Medical University Hospital, Taipei, Taiwan

    Ruei-Ming Chen

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  1. Chia-Yu Chang
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Correspondence to Ruei-Ming Chen.

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Chang, CY., Lui, TN., Lin, JW. et al. Roles of microRNA-1 in hypoxia-induced apoptotic insults to neuronal cells. Arch Toxicol 90, 191–202 (2016). https://doi.org/10.1007/s00204-014-1364-x

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  • DOI: https://doi.org/10.1007/s00204-014-1364-x

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