Hypoxia-inducible factor-1α mediates up-regulation of neprilysin by histone deacetylase-1 under hypoxia condition in neuroblastoma cells

Authors

  • Hecheng Wang,

    1. Neuroscience Research Institute & Department of Neurobiology, Key Laboratory for Neuroscience, Ministry of Education & Ministry of Public Health, Health Science Center, Peking University, Beijing, China
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  • Miao Sun,

    Corresponding author
    1. Neuroscience Research Institute & Department of Neurobiology, Key Laboratory for Neuroscience, Ministry of Education & Ministry of Public Health, Health Science Center, Peking University, Beijing, China
    • Address correspondence and reprint requests to Dr Miao Sun, Peking University HSC, 38 Xueyuan Road, Hai Dian District, Beijing 100191, China. Email: Breeze0123@gmail.com;

      Dr Weizhong Xiao, Peking University Third Hospital, Beijing 100191, China. Email: weizhong_xiao@163.com;

      Dr Xuefei Wu, Dalian Medical University, Dalian 116044, China. Email: wuxuefei1973@126.com;

      Dr Dehua Chui, Peking University HSC, 38 Xueyuan Road, Hai Dian District, Beijing 100191, China. Email: dchui@bjmu.edu.cn

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  • Huan Yang,

    1. Neuroscience Research Institute & Department of Neurobiology, Key Laboratory for Neuroscience, Ministry of Education & Ministry of Public Health, Health Science Center, Peking University, Beijing, China
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  • Xiaosheng Tian,

    1. Neuroscience Research Institute & Department of Neurobiology, Key Laboratory for Neuroscience, Ministry of Education & Ministry of Public Health, Health Science Center, Peking University, Beijing, China
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  • Yawei Tong,

    1. Neuroscience Research Institute & Department of Neurobiology, Key Laboratory for Neuroscience, Ministry of Education & Ministry of Public Health, Health Science Center, Peking University, Beijing, China
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  • Ting Zhou,

    1. Neuroscience Research Institute & Department of Neurobiology, Key Laboratory for Neuroscience, Ministry of Education & Ministry of Public Health, Health Science Center, Peking University, Beijing, China
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  • Tao Zhang,

    1. Neuroscience Research Institute & Department of Neurobiology, Key Laboratory for Neuroscience, Ministry of Education & Ministry of Public Health, Health Science Center, Peking University, Beijing, China
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  • Yaoyun Fu,

    1. Neuroscience Research Institute & Department of Neurobiology, Key Laboratory for Neuroscience, Ministry of Education & Ministry of Public Health, Health Science Center, Peking University, Beijing, China
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  • Xiangyang Guo,

    1. Peking University Third Hospital, Beijing, China
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  • Dongsheng Fan,

    1. Peking University Third Hospital, Beijing, China
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  • Albert Yu,

    1. Neuroscience Research Institute & Department of Neurobiology, Key Laboratory for Neuroscience, Ministry of Education & Ministry of Public Health, Health Science Center, Peking University, Beijing, China
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  • Ming Fan,

    1. Department of Brain Protection and Plasticity, Institute of Basic Medical Sciences, Beijing, China
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  • Xuefei Wu,

    Corresponding author
    1. Dalian Medical University, Dalian, China
    • Address correspondence and reprint requests to Dr Miao Sun, Peking University HSC, 38 Xueyuan Road, Hai Dian District, Beijing 100191, China. Email: Breeze0123@gmail.com;

      Dr Weizhong Xiao, Peking University Third Hospital, Beijing 100191, China. Email: weizhong_xiao@163.com;

      Dr Xuefei Wu, Dalian Medical University, Dalian 116044, China. Email: wuxuefei1973@126.com;

      Dr Dehua Chui, Peking University HSC, 38 Xueyuan Road, Hai Dian District, Beijing 100191, China. Email: dchui@bjmu.edu.cn

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  • Weizhong Xiao,

    Corresponding author
    1. Peking University Third Hospital, Beijing, China
    • Address correspondence and reprint requests to Dr Miao Sun, Peking University HSC, 38 Xueyuan Road, Hai Dian District, Beijing 100191, China. Email: Breeze0123@gmail.com;

      Dr Weizhong Xiao, Peking University Third Hospital, Beijing 100191, China. Email: weizhong_xiao@163.com;

      Dr Xuefei Wu, Dalian Medical University, Dalian 116044, China. Email: wuxuefei1973@126.com;

      Dr Dehua Chui, Peking University HSC, 38 Xueyuan Road, Hai Dian District, Beijing 100191, China. Email: dchui@bjmu.edu.cn

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  • Dehua Chui

    Corresponding author
    1. Neuroscience Research Institute & Department of Neurobiology, Key Laboratory for Neuroscience, Ministry of Education & Ministry of Public Health, Health Science Center, Peking University, Beijing, China
    2. Peking University Third Hospital, Beijing, China
    • Address correspondence and reprint requests to Dr Miao Sun, Peking University HSC, 38 Xueyuan Road, Hai Dian District, Beijing 100191, China. Email: Breeze0123@gmail.com;

      Dr Weizhong Xiao, Peking University Third Hospital, Beijing 100191, China. Email: weizhong_xiao@163.com;

      Dr Xuefei Wu, Dalian Medical University, Dalian 116044, China. Email: wuxuefei1973@126.com;

      Dr Dehua Chui, Peking University HSC, 38 Xueyuan Road, Hai Dian District, Beijing 100191, China. Email: dchui@bjmu.edu.cn

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Abstract

Hypoxia-inducible factor (HIF)-1 is the key transcriptional activator mediating both adaptive and pathological responses to hypoxia. The purpose of this study was to find the role of HIF-1 in regulating neprilysin (NEP) at the early stage of hypoxia and explore the underlying mechanism. In this study, we demonstrated that both NEP mRNA and protein levels in neuroblastoma cells were elevated in early stages of hypoxia. Over-expression of HIF-1α gene increased NEP mRNA/protein levels, as well as enzyme activity while knockdown of HIF-1α decreased them. Meanwhile, HIF-1α was shown to bind to histone deacetylase (HDAC)-1 and reduced the association of HDAC-1 with NEP promoter, thus activating NEP gene transcription in a de-repression way. In summary, our results indicated that hypoxia in the early stages would up-regulate NEP expression, in which interaction of HIF-1α and HDAC-1 may play a role. This study suggested that NEP up-regulation might be an adaptive response to hypoxia, which was mediated by HIF-1α binding to HDAC-1 at the early stage of hypoxia.

image

HIF-1 binded to and disassociated HDAC-1 from NEP promoter, activating NEP gene expression at early stage of hypoxia. HDAC-1 protein level was elevated at late stage of hypoxia that exceeded the binding capacity of HIF-1 to prevent association of HDAC-1 from NEP promoter, leading to suppression of NEP.

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