Abstract
Long non-coding RNAs (lncRNAs) have emerged as a new class of gene expression regulators playing key roles in many biological and pathophysiological processes. Here, we identify cardiac conduction regulatory RNA (CCRR) as an antiarrhythmic lncRNA. CCRR is downregulated in a mouse model of heart failure (HF) and in patients with HF, and this downregulation slows cardiac conduction and enhances arrhythmogenicity. Moreover, CCRR silencing induces arrhythmias in healthy mice. CCRR overexpression eliminates these detrimental alterations. HF or CCRR knockdown causes destruction of intercalated discs and gap junctions to slow longitudinal cardiac conduction. CCRR overexpression improves cardiac conduction by blocking endocytic trafficking of connexin43 (Cx43) to prevent its degradation via binding to Cx43-interacting protein CIP85, whereas CCRR silence does the opposite. We identified the functional domain of CCRR, which can reproduce the functional roles and pertinent molecular events of full-length CCRR. Our study suggests CCRR replacement a potential therapeutic approach for pathological arrhythmias.
Highlights
Long non-coding RNAs have emerged as a new class of gene expression regulators playing key roles in many biological and pathophysiological processes
We conclude that conduction regulatory RNA (CCRR) is an antiarrhythmic Long non-coding RNAs (lncRNAs) that acts by maintaining functional myocardial syncytium and its downregulation serves as a mechanism for the electrical disturbances and contractile dysfunction typically found in heart failure (HF)
(3) On the contrary, overexpression of CCRR abrogates the conduction anomalies in the setting of HF, and CCRR was required for maintaining proper distribution of Cx43 in the intercalated discs by binding to CIP85 protein so as to prevent Cx43 from backward trafficking and subsequent degrading, which likely served as a downstream mechanism for the disruption of gap junction (Fig. 10)
Summary
Long non-coding RNAs (lncRNAs) have emerged as a new class of gene expression regulators playing key roles in many biological and pathophysiological processes. In order for heart to maintain efficient ejection of blood, cardiac muscles (cardiomyocytes) operate as a single functional syncytium, that is, they contract in unison[1] This is because individual cardiac muscle cells are connected by the highly organized intercalated discs where gap junctions are concentrated allowing for well-orchestrated spatial propagation of action potentials through tight cardiomyocyte–cardiomyocyte coupling. Long noncoding RNAs (lncRNAs) have emerged as a new player of gene expression regulation and coordination[6,7,8] These newly recognized regulatory molecules are mRNA-like transcripts ranging from 200 nt to 100 kb in length, featured by lack of protein-coding activity, yet can participate in many fundamental biological processes and pathophysiological events. CCRR replacement might be considered a prospective therapeutic strategy for arrhythmias under pathological conditions of the heart
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
