Aberrant dynamin 2-dependent Na+/H+ exchanger-1 trafficking contributes to cardiomyocyte apoptosis

Authors

  • Jun Li,

    1. Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai, China
    2. Institute of Medical Genetics, Tongji University, Shanghai, China
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    • These authors contributed equally to this work.
  • Liang Xu,

    1. Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai, China
    2. Institute of Medical Genetics, Tongji University, Shanghai, China
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    • These authors contributed equally to this work.
  • Jiangchuan Ye,

    1. Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai, China
    2. Department of Cardiology, East Hospital, Tongji University School of Medicine, Shanghai, China
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    • These authors contributed equally to this work.
  • Xiang Li,

    1. Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai, China
    2. Department of Cardiology, East Hospital, Tongji University School of Medicine, Shanghai, China
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    • These authors contributed equally to this work.
  • Dasheng Zhang,

    1. Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai, China
    2. Institute of Medical Genetics, Tongji University, Shanghai, China
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  • Dandan Liang,

    1. Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai, China
    2. Institute of Medical Genetics, Tongji University, Shanghai, China
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  • Xinran Xu,

    1. Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai, China
    2. Institute of Medical Genetics, Tongji University, Shanghai, China
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  • Man Qi,

    1. Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai, China
    2. Department of Cardiology, East Hospital, Tongji University School of Medicine, Shanghai, China
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  • Changming Li,

    1. Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai, China
    2. Department of Cardiology, East Hospital, Tongji University School of Medicine, Shanghai, China
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  • Hong Zhang,

    1. Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai, China
    2. Institute of Medical Genetics, Tongji University, Shanghai, China
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  • Jing Wang,

    1. Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai, China
    2. Department of Cardiology, East Hospital, Tongji University School of Medicine, Shanghai, China
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  • Yi Liu,

    1. Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai, China
    2. Institute of Medical Genetics, Tongji University, Shanghai, China
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  • Yuzhen Zhang,

    1. Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai, China
    2. Institute of Medical Genetics, Tongji University, Shanghai, China
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  • Zhaonian Zhou,

    1. Laboratory of Hypoxic Cardiovascular Physiology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
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  • Xingqun Liang,

    1. Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai, China
    2. Institute of Medical Genetics, Tongji University, Shanghai, China
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  • Jue Li,

    1. Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai, China
    2. Institute of Medical Genetics, Tongji University, Shanghai, China
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  • Luying Peng,

    1. Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai, China
    2. Institute of Medical Genetics, Tongji University, Shanghai, China
    3. Department of Pathology and Pathophysiology, Tongji University School of Medicine, Shanghai, China
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  • Weidong Zhu,

    1. Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai, China
    2. Institute of Medical Genetics, Tongji University, Shanghai, China
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  • Yi-Han Chen

    Corresponding author
    1. Institute of Medical Genetics, Tongji University, Shanghai, China
    2. Department of Cardiology, East Hospital, Tongji University School of Medicine, Shanghai, China
    3. Department of Pathology and Pathophysiology, Tongji University School of Medicine, Shanghai, China
    • Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai, China
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Correspondence to: Yi-Han CHEN, Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.

Tel.: +86-21-65989086

Fax: +86-21-65989086

E-mail: yihanchen@tongji.edu.cn

Abstract

Sarcolemmal Na+/H+ exchanger 1 (NHE1) activity is essential for the intracellular pH (pHi) homeostasis in cardiac myocytes. Emerging evidence indicates that sarcolemmal NHE1 dysfunction was closely related to cardiomyocyte death, but it remains unclear whether defective trafficking of NHE1 plays a role in the vital cellular signalling processes. Dynamin (DNM), a large guanosine triphosphatase (GTPase), is best known for its roles in membrane trafficking events. Herein, using co-immunoprecipitation, cell surface biotinylation and confocal microscopy techniques, we investigated the potential regulation on cardiac NHE1 activity by DNM. We identified that DNM2, a cardiac isoform of DNM, directly binds to NHE1. Overexpression of a wild-type DNM2 or a dominant-negative DNM2 mutant with defective GTPase activity in adult rat ventricular myocytes (ARVMs) facilitated or retarded the internalization of sarcolemmal NHE1, whereby reducing or increasing its activity respectively. Importantly, the increased NHE1 activity associated with DNM2 deficiency led to ARVMs apoptosis, as demonstrated by cell viability, terminal deoxynucleotidyl transferase–mediated dUTP nick-end labelling assay, Bcl-1/Bax expression and caspase-3 activity, which were effectively rescued by pharmacological inhibition of NHE1 with zoniporide. Thus, our results demonstrate that disruption of the DNM2-dependent retrograde trafficking of NHE1 contributes to cardiomyocyte apoptosis.

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