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

Yong Zhang, Lihua Sun, Lina Xuan, Zhenwei Pan, Xueling Hu, Hongyu Liu, Yunlong Bai, Lei Jiao, Zhange Li, Lina Cui, Xiaoxue Wang, Siqi Wang, Tingting Yu, Bingbing Feng, Ying Guo, Zonghong Liu, Weixin Meng, Hequn Ren, Jiyuan Zhu, Xuyun Zhao, Chao Yang, Ying Zhang, Chaoqian Xu, Zhiguo Wang, Yanjie Lu, Hongli Shan, Baofeng Yang
Nature Communications2018
Long non-coding RNAs (lncRNAs) have emerged as a new class of gene expression reg- ulators 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 det- rimental 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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