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
Up-frameshift 1(UPF1),as the most critical factor in nonsense-mediated messenger RNA(mRNA)decay(NMD),regulates tumor-associated molecular pathways in many cancers.However,the role of UPF1 in lung adenocarcinoma(LUAD)a...Up-frameshift 1(UPF1),as the most critical factor in nonsense-mediated messenger RNA(mRNA)decay(NMD),regulates tumor-associated molecular pathways in many cancers.However,the role of UPF1 in lung adenocarcinoma(LUAD)amino acid metabolism remains largely unknown.In this study,we found that UPF1 was significantly correlated with a portion of amino acid metabolic pathways in LUAD by integrating bioinformatics and metabolomics.We further confirmed that UPF1 knockdown inhibited activating transcription factor 4(ATF4)and Ser51 phosphorylation of eukaryotic translation initiation factor 2α(eIF2α),the core proteins in amino acid metabolism reprogramming.In addition,UPF1 promotes cell proliferation by increasing the amino-acid levels of LUAD cells,which depends on the function of ATF4.Clinically,UPF1 mRNA expression is abnormal in LUAD tissues,and higher expression of UPF1 and ATF4 was significantly correlated with poor overall survival(OS)in LUAD patients.Our findings reveal that UPF1 is a potential regulator of tumor-associated amino acid metabolism and may be a therapeutic target for LUAD.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.
基金supported by the National Natural Science Foundation of China(Nos.81803886,81774078,and 21907093)。
文摘Up-frameshift 1(UPF1),as the most critical factor in nonsense-mediated messenger RNA(mRNA)decay(NMD),regulates tumor-associated molecular pathways in many cancers.However,the role of UPF1 in lung adenocarcinoma(LUAD)amino acid metabolism remains largely unknown.In this study,we found that UPF1 was significantly correlated with a portion of amino acid metabolic pathways in LUAD by integrating bioinformatics and metabolomics.We further confirmed that UPF1 knockdown inhibited activating transcription factor 4(ATF4)and Ser51 phosphorylation of eukaryotic translation initiation factor 2α(eIF2α),the core proteins in amino acid metabolism reprogramming.In addition,UPF1 promotes cell proliferation by increasing the amino-acid levels of LUAD cells,which depends on the function of ATF4.Clinically,UPF1 mRNA expression is abnormal in LUAD tissues,and higher expression of UPF1 and ATF4 was significantly correlated with poor overall survival(OS)in LUAD patients.Our findings reveal that UPF1 is a potential regulator of tumor-associated amino acid metabolism and may be a therapeutic target for LUAD.
