Cardiac lipotoxicity may induce cardiomyocyte apoptosis, eventually leading to myocardial dysfunction and heart failure. This study investigated whether and how junctophilin-2 (JPH2) plays a role in palmitate-induced apoptosis in cardiomyocytes. Here, we found palmitate incubation reduced JPH2 protein levels, increased cytosolic Ca2+ and induced apoptosis in cardiomyocytes. JPH2 over-expression prevented the increased cytosolic Ca2+ and apoptosis in palmitate-stimulated cardiomyocytes. JPH2 over-expression also attenuated palmitate-induced CCAAT-enhancer-binding protein homologous protein (CHOP) expression and CHOP deletion alleviated palmitate-induced apoptosis. Furthermore, blocking Ca2+ release from ryanodine receptor-2 (RyR2) prevented palmitate-stimulated CHOP induction and apoptosis. Additionally, JPH2 silencing elevated cytosolic Ca2+, induced CHOP expression and apoptosis in cardiomyocytes; these effects of JPH2 silencing were inhibited by blocking Ca2+ release from RyR2. In summary, we demonstrate that JPH2 attenuates palmitate-induced apoptosis by reducing Ca2+ release from RyR2 and preventing CHOP expression in cardiomyocytes. Thus, targeting JPH2 may represent a new therapeutic strategy to treat cardiac lipotoxicity
