FKBP12.6-Mediated Stabilization of Calcium-Release Channel (Ryanodine Receptor) as a Novel Therapeutic Strategy Against Heart Failure

Abstract

Background-The development of heart failure is tightly correlated with a decrease in the stoichiometric ratio for FKBP12.6 binding to the ryanodine receptor (RyR) in the sarcoplasmic reticulum (SR). We report that a new drug, the 1,4-benzothiazepine derivative JTV519, reverses this pathogenic process. JTV519 is known to have a protective effect against Ca 2ϩ overload-induced myocardial injury. Methods and Results-Heart failure was produced by 4 weeks of rapid right ventricular pacing, with or without JTV519; SR were then isolated from dog left ventricular (LV) muscles. First, in JTV519-treated dogs, no signs of heart failure were observed after 4 weeks of chronic right ventricular pacing, LV systolic and diastolic functions were largely preserved, and LV remodeling was prevented. Second, JTV519 acutely inhibited both the FK506-induced Ca 2ϩ leak from RyR in normal SR and the spontaneous Ca 2ϩ leak in failing SR. Third, there was no abnormal Ca 2ϩ leak in SR vesicles isolated from JTV519-treated hearts. Fourth, in JTV519-treated hearts, both the stoichiometry of FKBP12.6 binding to RyR and the amount of RyR-bound FKBP12.6 were restored toward the values seen in normal SR. Fifth, in JTV519-untreated hearts, RyR was PKA-hyperphosphorylated, whereas it was reversed in JTV519-treated hearts, returning the channel phosphorylation toward the levels seen in normal hearts. Conclusions-During the development of experimental heart failure, JTV519 prevented the amount of RyR-bound FKBP12.6 from decreasing. This in turn reduced the abnormal Ca 2ϩ leak through the RyR, prevented LV remodeling, and led to less severe heart failure.

Rodent models of heart failure: an updated review

“…Knockout Cardiac hypertrophy Disregulation of Ca 2? release in the myocytes A benzothiazepine derivative JTV519 prevents the decrease of RyR2-bound FKBP12.6, improves cardiac function and avoids cardiac remodeling in a canine model of CHF raising the question of it could be a novel therapeutic target [321] Gene targeting has often been heralded as being more precise and useful than transgenesis. When coupled with tissue-or cell type-specific methodologies via Cre-lox technology, gene targeting offers a precise way of introducing specific mutations that will only be expressed in a defined cell type at a particular developmental time.…”

2APB- and JTV519(K201)-sensitive micro Ca2+ waves in arrhythmogenic Purkinje cells that survive in infarcted canine heart

“…11 Thus, we determined the effects of JTV519(K201) superfusion on μCaiTs in five IZPCs. Figure 5 shows the effects of the drug.…”

CPU86017, a berberine derivative, attenuates cardiac failure through normalizing calcium leakage and downregulated phospholamban and exerting antioxidant activity

“…Thus, a restriction of calcium influx by the calcium antagonism of CPU86017 contributes in part to attenuating ISO-induced HF and arrhythmogenesis. Furthermore, calcium leakage can be blocked by intervention with compound JTV519 [39] , which shares a similar profile of multi-channel blocking activity including an inhibitory effect on Ca 2+ influx with CPU86017 [40] . Furthermore, an antioxidative activity is effective in ameliorating abnormal PLB and calcium leakage during septic shock due to improved mitochondria activity [41] .…”