Deficiency of LncRNA-CIRBIL promotes J-wave syndrome by enhancing transmural heterogeneity of Ito current

Abstract Transmural heterogeneity of Ito current is a major cause of J-wave syndrome (JWS), while the underlying molecular mechanisms remain elusive. The present study aims to explore the influence of Cardiac Injury-Related Bclaf1-Interacting LncRNA (lncCIRBIL) on cardiac J-wave syndrome and to delineate the molecular mechanisms. The plasma level of lncCIRBIL was reduced in JWS patients and cold-induced JWS mice. Knockout of lncCIRBIL increased the frequency of J-wave and the susceptibility to ventricular arrhythmia in mice. The transmural difference of KCND2 and Ito currents were dramatically increased in the right ventricle, but not the left ventricle of lncCIRBIL-KO mice. In contrast, cardiomyocyte-specific transgenic overexpression of lncCIRBIL produced the opposite effects. The human homologous conserved fragment of lncCIRBIL (hcf-CIRBIL) reduced Ito, downregulated action potential notch and prolonged APD20 in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM). LncCIRBIL titrates the transmural heterogeneity of KCND2 by regulating UPF1 mediated mRNA decay. Inhibition of lncCIRBIL promoted J-wave syndrome by enhancing the transmural heterogeneity of Ito in the right ventricle. These findings imply that lncCIRBIL represents a potential therapeutic target for J-wave syndrome.