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

2018; Impact Journals LLC; Volume: 9; Issue: 18 Linguagem: Inglês

10.18632/oncotarget.24449

1949-2553

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

Coenzyme Q10 studies and effects

// Yuko Iwata 1 , Yoshimi Katayama 2, 5 , Yasushi Okuno 3 and Shigeo Wakabayashi 4, 6 1 Departments of Molecular Physiology and Clinical Research, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan 2 Pharmacological Research Laboratories, Drug Safety Testing Center Co., Ltd., Higashimatsuyama, Saitama, Japan 3 Department of Clinical System Onco-Informatics, Graduate School of Medicine, Kyoto University, Kyoto, Japan 4 Departments of Molecular Physiology and Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan 5 Present affiliation: Biological Research Laboratories, Nissan Chemical Industries, Ltd, Shiraoka, Saitama, Japan 6 Present 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 Ca 2+ -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 Ca 2+ entry through both mouse and human TRPV2, with IC 50 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 Ca 2+ 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.