Fixing Ca2+ Leak through the Ryanodine Receptor Inhibits Cardiomyocyte Hypertrophy and Relaxation Impairment in the Compensated Pressure-overloaded Heart

We investigated whether transverse aortic constriction (TAC)-induced pressure overload caused Ca2+ leak through ryanodine receptor (RyR2) even in compensated pressure-overloaded hearts, and whether chronic administration of dantrolene, a RyR2 stabilizer, inhibited the cardiomyocyte hypertrophy and dysfunction by stopping the Ca2+leak. Methods: We developed compensated hypertrophy model by 2 weeks-TAC in mice. TAC mice were divided into dantrolene-treated (DAN) group and vehicle (non-DAN) group. Then, cardiomyocytes were isolated from hearts, and diastolic Ca2+ spark assay, simultaneous Ca2+ transient (CaT) and cell shortening (CS) assay were examined. Results: Ca2+ leak through RyR2 was observed even in the early compensated pressure-overloaded heart. Two weeks-TAC caused cardiomyocyte hypertrophy, which was inhibited by chronic dantrolene administration. Ca2+ spark frequency (CaSF) was higher in TAC than in Sham, which was inhibited by chronic dantrolene treatment. %CS and time to peak as an index of contractility were normally preserved in both DAN and non-DAN groups. However, time from peak to 70% decline as an index of relaxation was significantly longer in non-DAN group than in DAN group. Conclusions: Dantrolene restores the cardiomyocyte dysfunction and inhibits the cardiomyocyte hypertrophy by inhibiting the aberrant Ca2+ leak through RyR2 in the compensated pressure-overloaded heart.