Novel inhibitor candidates of TRPV2 prevent damage of dystrophic myocytes and ameliorate against dilated cardiomyopathy in a hamster model

  • Iwata, Yuko
    Departments of Molecular Physiology and Clinical Research, National Cerebral and Cardiovascular Center Research Institute, Suita
  • Katayama, Yoshimi
    Pharmacological Research Laboratories, Drug Safety Testing Center Co., Ltd.
  • Okuno, Yasushi
    Department of Clinical System Onco-Informatics, Graduate School of Medicine, Kyoto University
  • Wakabayashi, Shigeo
    Departments of Molecular Physiology and Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita


Transient receptor potential cation channel, subfamily V, member 2 (TRPV2) is a principal candidate for abnormal Ca²⁺-entry pathways, which is a potential target for therapy of muscular dystrophy and cardiomyopathy. Here, an in silico drug screening and the following cell-based screening to measure the TRPV2 activation were carried out in HEK293 cells expressing TRPV2 using lead compounds (tranilast or SKF96365) and off-patent drug stocks. We identified 4 chemical compounds containing amino-benzoyl groups and 1 compound (lumin) containing an ethylquinolinium group as candidate TRPV2 inhibitors. Three of these compounds inhibited Ca²⁺ entry through both mouse and human TRPV2, with IC₅₀ of less than 10 μM, but had no apparent effect on other members of TRP family such as TRPV1 and TRPC1. Particularly, lumin inhibited agonist-induced TRPV2 channel activity at a low dose. These compounds inhibited abnormally increased Ca²⁺ influx and prevented stretch-induced skeletal muscle damage in cultured myocytes from dystrophic hamsters (J2N-k). Further, they ameliorated cardiac dysfunction, and prevented disease progression in vivo in the same J2N-k hamsters developing dilated cardiomyopathy as well as muscular dystrophy. The identified compounds described here are available as experimental tools and represent potential treatments for patients with cardiomyopathy and muscular dystrophy.


  • Oncotarget

    Oncotarget 9 (18), 14042-14057, 2018

    Impact Journals, LLC

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