Deficiency of Lnc RNA-CIRBIL promotes J-wave syndrome by enhancing transmural heterogeneity of Ito current:LncCIRBIL regulates J-wave syndrome via UPF1
Xuexin Jin
Wenbo Ma
Jinyun Guo
Yueying Qu
Haiyu Gao
Dechun Yin
Desheng Li
Ling Shi
Jialiang Li
Jiudong Ma
Lingmin Zhang
Hongli Shan
Yanjie Lu
Yue Li
Dongmei Gong
Zhenwei Pan
Abstract：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 protein 1 (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.
Keywords：long noncoding RNAJ-wave syndromeKCND2up-frameshift protein1arrhythmia
Publication Date：2025-09-30
Online Publishing Date：2025-11-28(First online date of this platform, not the publication date of the document)
Pages：13( 157-169 )