Ranolazine rescue the heart failure phenotype of PLN-deficient human pluripotent stem cells derived cardiomyocytes

Phospholamban(PLN) is a key regulator of SR function and cardiac contractility. The PLN-deficient mice showed enhanced myocardial performance but PLN deficiency in human can lead to dilated cardiomyopathy (DCM) or heart failure (HF). Due to the lack of human experimental models, the mechanisms of the phenotypic difference about PLN defects between human and mice remain unclear. In this study, we generated a knockout PLN human embryonic stem cell (hiPSC) H9 cell line using CRISPR/Cas9 mediated gene disruption. PLN knockout hiPSCs-CMs present increased contractility at day 30, but progress into a heart failure phenotype at day 60 with reduced contractility, mitochondrial damage, increasing ROS generation, imbalance of cellular energy metabolism and impaired Ca2+ handling. Moreover, the addition of ranolazine to PLN knockout hiPSCs-CMs at day 60 can partially restore Ca2+ handling disorders and cellular energy metabolism, alleviating the phenotype of heart failure caused by PLN knockout, suggesting that the disorder of intracellular Ca2+ transport and the imbalance of cellular energy metabolism are the primary mechanisms for pathogenesis of PLN deficiency. To summarize, PLN-deficient hiPSC-CMs recapitulate the pathogenesis of HF, providing an important human experimental model for investigation of PLN-associated pathogenesis. More importantly, ranolazine may be a potential drug for the treatment of disease caused by PLN deficiency through correction of the autonomous dysfunction of Ca2+ handling and cellular energy metabolism.