Deficiency of LncRNA-CIRBIL promotes J-wave syndrome by enhancing transmural heterogeneity of I_to current: LncCIRBIL regulates J-wave syndrome via UPF1

Abstract

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 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.

Keywords

long noncoding RNA / J-wave syndrome / KCND2 / up-frameshift protein1 / arrhythmia

Acknowledgements

Not applicable.

Research ethics

The use of human samples was approved by the Institutional Review Board of College of Pharmacy, Harbin Medical University (IRB2007821) and complies with the requirements of the Declaration of Helsinki. All protocols for animal experiments were approved by the Committee for Animal Experimentation of Harbin Medical University (IRB2007821) and complies with the requirements of the Declaration of Helsinki.

Informed consent

Written informed consent of each participant was obtained.

Author contributions

Pan Z W, Gong D M and Li Y conceived the study concept. Jin X X, Ma W B, Guo J Y, Qu Y Y, Gao H Y, Yin D C, Li D S, Shi L, Li J L, Ma J D, Zhang L M, Shan H L, Lu Y J performed the experimental studies. Jin X X, Ma W B and Guo J Y carried out the data analysis. Pan Z W, Jin X X and Ma W B wrote the manuscript. Pan Z W, Jin X X and Yin D C provided the funding. All authors reviewed the manuscript. Jin X X, Ma W B and Guo J Y contributed equally to this work.

Use of large language models, AI and machine learning tools

Not applicable.

Conflict of interests

Pan Z W is an Editorial Board Member of Frigid Zone Medicine. The article was subject to the journal's standard procedures, with peer review handled independently of this Member and his research groups.

Data availability

The data are presented in the study and further inquiries can be directed to the corresponding author.

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