Research in the inhibitory effect of sarcoplasmic reticulum Ca release channel stabilizer on the development of heart failure

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In heart failure, abnormal function of sarcoplasmic reticulum (SR) is one of the major pathogenic mechanisms in heart failure. Here, we assessed the effects of 1,4-benzothiazepine derivative JTV519 (intracellular Ca2+ modulator) and propranolol on cardiac and SR functions. SR vesicles were isolated from dog LV muscles {normal (N), n=11; 4-weeks rapid RV pacing with or without JTV519 (JT:14.4 mg/Kg/day) or propranolol (PL:0.05mg/kg/day) [untreated: n=10, JT(+): n=10, PL(+): n=10, respectively]}. 1) In either JT(+) or PL(+), cardiac function was improved compared with untreated group. 2) Abnormal SR Ca2+ leak was found in untreated failing SR. A benzothiazepine Ca^<2+> antagonist diltiazem as well as JTV519 acutely inhibited this Ca^<2+> leak in failing SR (IC50= 0.3μM, 0.03μM, respectively), and neither nifedipine nor verapamil affected the Ca^<2+> leak. There was no abnormal SR Ca^<2+> leak either in JT(+) and PL(+). 3) Both JTV519 and propranolol prevented the decrease in the stoichiometry of RyR vs FKBP12.6 assessed by [^3H]ryanodine and [^3H]FK 506-bindng assays [1:3.6 in normal, 1:1.3 in untreated, 1:3.6 in JT(+), 1:2.4 in PL(+)]. 4) In untreated group, RyR was PKA- hyperphosphorylated, whereas it was reversed both in JT(+) and in PL(+). 5) The amount of RyR-bound FKBP12.6 was tremendously less in untreated group than normal RyR, whereas it was reversed both in JT(+) and PL(+). 6) RyR was labeled in a site-directed fashion with the fluorescent conformational probe methylcoumarin acetate (MCA). In both J(+) and P(+), the level of MCA fluorescence, which was higher in untreated group, was decreased back towards normal, suggesting the improvement of RyR conformational state by both treatments. Both JTV519 and proplanolol improved cardiac function and attenuated LV remodeling by ameliorating the defective interaction of FKBP12.6 with RyR through restoration of PKA-hyperphosphorylation of RyR and the following conformational change of RyR.