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.
Highlights
Dilated cardiomyopathy (DCM) is a severe disorder characterised by ventricular dilation and cardiac dysfunction [1,2,3]
Chronic elevation in cytosolic Ca2+ concentration ([Ca2+]i) beneath the sarcolemma and within other cellular compartments has been reported in skeletal muscle fibres and cultured myotubes derived from Duchenne muscular dystrophy patients and mdx mice [10,11,12]. [Ca2+]i in muscle fibre cells is regulated by multiple Ca2+-permeable channels, Ca2+ pumps, and transporters in the plasma membrane and sarcoplasmic reticulum, among which sarcolemmal Ca2+-permeable channels and mechanosensitive, nonselective cation channels contribute to abnormal Ca2+ handling in dystrophic myocytes [13, 14]
We previously showed that δ-SG-deficient myocytes are highly susceptible to mechanical stretch and enhanced Ca2+ influx via the stretch-activated nonselective Ca2+ channel [15] and identified transient receptor potential cation channel, subfamily V, member 2 (TRPV2) as a candidate factor in Ca2+ entry pathways whose activation results in perturbation of Ca2+ handling and subsequent muscular degeneration [16]
Summary
Dilated cardiomyopathy (DCM) is a severe disorder characterised by ventricular dilation and cardiac dysfunction [1,2,3]. Enhanced susceptibility to muscle damage is observed in dystrophic animals, such as dystrophindeficient mdx mice and δ-sarcoglycan (SG)-deficient J2N-k hamsters, which exhibit cardiac and skeletal abnormalities similar to those observed in human patients with Duchenne or limb-girdle muscular dystrophy. Chronic elevation in cytosolic Ca2+ concentration ([Ca2+]i) beneath the sarcolemma and within other cellular compartments has been reported in skeletal muscle fibres and cultured myotubes derived from Duchenne muscular dystrophy patients and mdx mice [10,11,12]. [Ca2+]i in muscle fibre cells is regulated by multiple Ca2+-permeable channels, Ca2+ pumps, and transporters in the plasma membrane and sarcoplasmic reticulum, among which sarcolemmal Ca2+-permeable channels ( known as Ca2+-specific leak channels) and mechanosensitive, nonselective cation channels contribute to abnormal Ca2+ handling in dystrophic myocytes [13, 14]. Because the effective doses of known TRPV2 inhibitors are high (>10–100 μM), while the drugs are relatively unselective, more potent and specific TRPV2 inhibitors are needed to confirm whether TRPV2 is an effective drug target for the treatment of patients with DCM and related disorders
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