Ranolazine rescues the heart failure phenotype of PLN-deficient human pluripotent stem cell-derived cardiomyocytes

Abstract

Phospholamban (PLN) is a key regulator that controls the function of the sarcoplasmic reticulum (SR) and is required for the regulation of cardiac contractile function. Although PLN-deficient mice demonstrated improved cardiac function, PLN loss in humans can result in dilated cardiomyopathy (DCM) or heart failure (HF). The CRISPR-Cas9 technology was used to create a PLN knockout human induced pluripotent stem cell (hiPSC) line in this study. PLN deletion hiPSCs-CMs had enhanced contractility at day 30, but proceeded to a cardiac failure phenotype at day 60, with decreased contractility, mitochondrial damage, increased ROS production, cellular energy metabolism imbalance, and poor Ca²⁺ handling. Furthermore, adding ranolazine to PLN knockout hiPSCs-CMs at day 60 can partially restore Ca²⁺ handling disorders and cellular energy metabolism, alleviating the PLN knockout phenotype of HF, implying that the disorder of intracellular Ca²⁺ transport and the imbalance of cellular energy metabolism are the primary mechanisms for PLN deficiency pathogenesis.

Keywords: heart failure; phospholamban knockout; ranolazine.