Oncotarget

Research Papers: Gerotarget (Focus on Aging):

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

Yuko Iwata _, Yoshimi Katayama, Yasushi Okuno and Shigeo Wakabayashi

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Oncotarget. 2018; 9:14042-14057. https://doi.org/10.18632/oncotarget.24449

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Abstract

Yuko Iwata1, Yoshimi Katayama2,5, Yasushi Okuno3 and Shigeo Wakabayashi4,6

1Departments of Molecular Physiology and Clinical Research, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan

2Pharmacological Research Laboratories, Drug Safety Testing Center Co., Ltd., Higashimatsuyama, Saitama, Japan

3Department of Clinical System Onco-Informatics, Graduate School of Medicine, Kyoto University, Kyoto, Japan

4Departments of Molecular Physiology and Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan

5Present affiliation: Biological Research Laboratories, Nissan Chemical Industries, Ltd, Shiraoka, Saitama, Japan

6Present affiliation: Department of Pharmocology, Osaka Medical Collage, Takatsuki, Osaka, Japan

Correspondence to:

Yuko Iwata, email: yukoiwat@ncvc.go.jp

Keywords: cardiomyopathy; muscular dystrophy; Ca2+ influx; Ca2+-permeable channel; therapy; Gerotarget

Received: January 26, 2018     Accepted: February 01, 2018     Epub: February 08, 2018     Published: March 06, 2018

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.


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