Background:Transmural heterogeneity of the transient outward potassium current(I_(to))is a major contributor to J-wave syndrome(JWS).However,the underlying molecular mechanisms remain elusive.The present study aimed t...Background:Transmural heterogeneity of the transient outward potassium current(I_(to))is a major contributor to J-wave syndrome(JWS).However,the underlying molecular mechanisms remain elusive.The present study aimed to investigate the role of cardiac injury-related bclaf1-interacting lncRNA(lncCIRBIL)in JWS and to delineate the molecular mechanisms.Methods:Whole-cell patch-clamp techniques were used to record ionic currents and action potentials(APs).Protein and mRNA expression related to I_(to)current were assessed.RNA immunoprecipitation,RNA Pulldown,mRNA stability,and decapping assays were performed to dissect the underlying mechanisms.Results:Plasma lncCIRBIL levels were significantly reduced in JWS patients and cold-induced JWS mice.Knockout of lncCIRBIL increased the incidence of J-wave and the susceptibility to ventricular arrhythmia in mice.In lncCIRBIL-deficient mice,the transmural gradient of Kv4.2 expression and I_(to)current density was markedly enhanced in the right ventricle,but not the left ventricle.In contrast,cardiomyocyte-specific transgenic overexpression of lncCIRBIL produced the opposite effects.In human induced pluripotent stem cell-derived cardiomyocytes(hiPSC-CMs),the conserved human homologous fragment of lncCIRBIL(hcf-CIRBIL)suppressed I_(to),attenuated the AP notch,and prolonged APD20.Mechanistically,lncCIRBIL directly binds to up-frameshift protein1(UPF1),promoting KCND2 mRNA decay by enhancing its decapping.Conclusions:LncCIRBIL modulates the transmural heterogeneity of KCND2 expression by regulating UPF1-mediated mRNA decay.Inhibition of lncCIRBIL exacerbates JWS by enhancing right ventricular I_(to)heterogeneity,whereas its overexpression exerts protective effects.These findings identify lncCIRBIL as a potential therapeutic target for J-wave syndrome.展开更多
基金supported by National Natural Science Foundation of China(82270320 to Yin D C82300280 to Jin X X+2 种基金82070344,81870295 to Pan Z W)HMU Marshal Initiative Funding(HMUMIF-21017 to Pan Z W)Excellent Young Medical Talents Training Fund of the First Affiliated Hospital of Harbin Medical University(No.2024YQ03 to Jin X X).
文摘Background:Transmural heterogeneity of the transient outward potassium current(I_(to))is a major contributor to J-wave syndrome(JWS).However,the underlying molecular mechanisms remain elusive.The present study aimed to investigate the role of cardiac injury-related bclaf1-interacting lncRNA(lncCIRBIL)in JWS and to delineate the molecular mechanisms.Methods:Whole-cell patch-clamp techniques were used to record ionic currents and action potentials(APs).Protein and mRNA expression related to I_(to)current were assessed.RNA immunoprecipitation,RNA Pulldown,mRNA stability,and decapping assays were performed to dissect the underlying mechanisms.Results:Plasma lncCIRBIL levels were significantly reduced in JWS patients and cold-induced JWS mice.Knockout of lncCIRBIL increased the incidence of J-wave and the susceptibility to ventricular arrhythmia in mice.In lncCIRBIL-deficient mice,the transmural gradient of Kv4.2 expression and I_(to)current density was markedly enhanced in the right ventricle,but not the left ventricle.In contrast,cardiomyocyte-specific transgenic overexpression of lncCIRBIL produced the opposite effects.In human induced pluripotent stem cell-derived cardiomyocytes(hiPSC-CMs),the conserved human homologous fragment of lncCIRBIL(hcf-CIRBIL)suppressed I_(to),attenuated the AP notch,and prolonged APD20.Mechanistically,lncCIRBIL directly binds to up-frameshift protein1(UPF1),promoting KCND2 mRNA decay by enhancing its decapping.Conclusions:LncCIRBIL modulates the transmural heterogeneity of KCND2 expression by regulating UPF1-mediated mRNA decay.Inhibition of lncCIRBIL exacerbates JWS by enhancing right ventricular I_(to)heterogeneity,whereas its overexpression exerts protective effects.These findings identify lncCIRBIL as a potential therapeutic target for J-wave syndrome.
