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

Abstract

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.

Journal

• Oncotarget

  Oncotarget 9 (18), 14042-14057, 2018

  Impact Journals, LLC

Keywords

• cardiomyopathy
• muscular dystrophy
• Ca2+ influx
• Ca2+-permeable channel
• therapy
• Gerotarget

Details

• CRID: 1050286428455312384
• NII Article ID: 120006892046
• ISSN: 19492553
• DOI: 10.18632/oncotarget.24449
• HANDLE: 2433/255569
• Web Site: https://www.oncotarget.com/lookup/doi/10.18632/oncotarget.24449
• Text Lang: en
• Article Type: journal article
• Data Source:
  • IRDB
  • Crossref
  • CiNii Articles
  • KAKEN