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Nat Commun. 2018 Oct 9;9(1):4176. doi: 10.1038/s41467-018-06637-9.

Long non-coding RNA CCRR controls cardiac conduction via regulating intercellular coupling.

Author information

1
Department of Pharmacology, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang, 150081, P.R. China.
2
Department of cardiovascular surgery, The First Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang, 150081, P.R. China.
3
Department of pathology, The First Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang, 150081, P.R. China.
4
Mu Danjiang Medical University Mu Danjiang, Heilongjiang, 157011, P.R. China.
5
Department of Pharmacology, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang, 150081, P.R. China. shanhongli@ems.hrbmu.edu.cn.
6
Department of Pharmacology, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang, 150081, P.R. China. yangbf@ems.hrbmu.edu.cn.
7
Department of Pharmacology and Therapeutics, Melbourne School of Biomedical Sciences, Faculty of Medicine, Dentistry and HealthSciences University of Melbourne, Melbourne, VIC 3010, Australia. yangbf@ems.hrbmu.edu.cn.

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.

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