Deficiency of Lnc RNA-CIRBIL promotes J-wave syndrome by enhancing transmural heterogeneity of Ito current:LncCIRBIL regulates J-wave syndrome via UPF1
Xuexin Jin1
Wenbo Ma2
Jinyun Guo2
Yueying Qu2
Haiyu Gao2
Dechun Yin3
Desheng Li2
Ling Shi3
Jialiang Li2
Jiudong Ma2
Lingmin Zhang2
Hongli Shan4
Yanjie Lu5
Yue Li6
Dongmei Gong2
Zhenwei Pan5
1.Department of Pharmacology(The Key Laboratory of Cardiovascular Research,Ministry of Education)at College of Pharmacy,Harbin Medical University,Harbin 150086,China;Department of Cardiology,the First Affiliated Hospital,Harbin Medical University,Harbin 150001,China2.Department of Pharmacology(The Key Laboratory of Cardiovascular Research,Ministry of Education)at College of Pharmacy,Harbin Medical University,Harbin 150086,China3.Department of Cardiology,the First Affiliated Hospital,Harbin Medical University,Harbin 150001,China4.Institute for Frontier Medical Technology,Shanghai University of Engineering Science,Shanghai 201620,China5.Department of Pharmacology(The Key Laboratory of Cardiovascular Research,Ministry of Education)at College of Pharmacy,Harbin Medical University,Harbin 150086,China;Research Unit of Noninfectious Chronic Diseases in Frigid Zone,Chinese Academy of Medical Sciences,Beijing 100730,China6.Department of Cardiology,the First Affiliated Hospital,Harbin Medical University,Harbin 150001,China;Key Laboratory of Cell Transplantation,The First Affiliated Hospital,Harbin Medical University,Harbin 150001,China
摘要：Background:Transmural heterogeneity of the transient outward potassium current(Ito)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 Ito 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 Ito 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 Ito,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 Ito heterogeneity,whereas its overexpression exerts protective effects.These findings identify lncCIRBIL as a potential therapeutic target for J-wave syndrome.
机标关键词：currentdeficiencyenhancingheterogeneityj-wavelnccirbilpromotesregulates
论文发表日期：2025-09-30
在线出版日期：2025-11-28（本平台首次上网日期，不代表文献的发表时间）
页数：13( 157-169 )
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