JTV-519 free base is a Ca2+-dependent blocker of SERCA that inhibits the ATPase activity [1]. JTV-519 free base can inhibit Na+, Ca2+ and K+ currents in guinea-pig ventricular cells, and exhibit cardioprotection against ischaemia/reperfusion injury in isolated rat hearts through the activation of protein kinase C [2]. JTV-519 free base has been widely used to alter the spatiotemporal properties of diastolic Ca2+ release and the associated diastolic contraction in rat ventricular cardiomyocytes [3].
In vitro, JTV-519 free base pretreatment (1μM) for 12 hours stabilized the RyR1 channel in flexor digitorum brevis muscle fibers of mice and reduced the delay in calcium reuptake induced by FK506 [4]. Treatment with 1μM JTV-519 free base for 7 days on HL-1 cells significantly reduced the calcium leak from the sarcoplasmic reticulum caused by hypoxia and increased the expression of the RyR2 gene[5]. The treatment of PC14 cells with 10μM JTV-519 free base for 72 hours significantly increased the platinum level in the cells and enhanced the cytotoxic effect of platinum on the cells[6].
In vivo, JTV-519 free base treatment via intravenous infusion (0.5mg/kg/h) for 2 hours inhibited the leak of cytosolic calcium from the sarcoplasmic reticulum in septic mice and improved cardiac function[7]. Intravenous infusion of JTV-519 free base (0.5mg/kg/h) for 4 weeks significantly improved the cardiac function of the myocardial infarction mouse model and reversed cardiac remodeling[8].
References:
[1] Darcy Y L, Diaz-Sylvester P L, Copello J A. K201 (JTV519) is a Ca2+-dependent blocker of SERCA and a partial agonist of ryanodine receptors in striated muscle[J]. Molecular Pharmacology, 2016, 90(2): 106-115.
[2] Nakaya H, Furusawa Y, Ogura T, et al. Inhibitory effects of JTV‐519, a novel cardioprotective drug, on potassium currents and experimental atrial fibrillation in guinea‐pig hearts[J]. British journal of pharmacology, 2000, 131(7): 1363-1372.
[3] Elliott E B, Hasumi H, Otani N, et al. K201 (JTV-519) alters the spatiotemporal properties of diastolic Ca2+ release and the associated diastolic contraction during β-adrenergic stimulation in rat ventricular cardiomyocytes[J]. Basic research in cardiology, 2011, 106(6): 1009-1022.
[4] Breckner A, Ganz M, Marcellin D, et al. Effect of Calstabin1 depletion on calcium transients and energy utilization in muscle fibers and treatment opportunities with RyR1 stabilizers[J]. PloS one, 2013, 8(11): e81277.
[5] Trinh M D, Fiserova I, Vacek L, et al. Hypoxia-Induced Sarcoplasmic Reticulum Ca2+ Leak Is Reversed by Ryanodine Receptor Stabilizer JTV-519 in HL-1 Cardiomyocytes[J]. Anatolian Journal of Cardiology, 2022, 26(6): 476.
[6] Nakamura T, Koizumi F, Kaneko N, et al. Reversal of Cisplatin Resistance by the 1, 4‐Benzothiazepine Derivative, JTV‐519[J]. Japanese journal of cancer research, 2001, 92(6): 597-602.
[7] Yang J, Zhang R, Jiang X, et al. Toll-like receptor 4–induced ryanodine receptor 2 oxidation and sarcoplasmic reticulum Ca2+ leakage promote cardiac contractile dysfunction in sepsis[J]. Journal of Biological Chemistry, 2018, 293(3): 794-807.
[8] Wehrens X H T, Lehnart S E, Reiken S, et al. Enhancing calstabin binding to ryanodine receptors improves cardiac and skeletal muscle function in heart failure[J]. Proceedings of the National Academy of Sciences, 2005, 102(27): 9607-9612.