LncRNA CCRR maintains Ca^(2+)homeostasis against myocardial infarction through the FTO-SERCA2a pathway  

作　　者：Hua Yang Lina Xuan Shengjie Wang Huishan Luo Xiaomeng Duan Jianjun Guo Shijia Cui Jieru Xin Junwei Hao Xiufang Li Jun Chen Feihan Sun Xiaolin Hu Siyun Li Ying Zhang Lei Jiao Baofeng Yang Lihua Sun 

机构地区：[1]Department of Pharmacology,Harbin Medical University(State Key Laboratory of Frigid Zone Cardiovascular Disease,the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China,Key Laboratory of Cardiovascular Research,Ministry of Education,Joint International Research Laboratory of Cardiovascular Medicine Research,Ministry of Education,China),College of Pharmacy,Harbin Medical University,Harbin 150081,China

出　　处：《Science China(Life Sciences)》2024年第8期1601-1619,共19页中国科学（生命科学英文版）

基　　金：supported by the National Natural Science Foundation of China(81970202,81903609,U21A20339);the Natural Science Foundation of Heilongjiang Province,China(LH2022H002);the Outstanding Young Talent Research Fund of College of Pharmacy,Harbin Medical University(2019-JQ-02);2021(the second batch)Research Funds for affiliated research institutes in Heilongjiang Province(CZKYF2021-2-C013).

摘　　要：Cardiac conduction regulatory RNA(CCRR)has been documented as an antiarrhythmic lncRNA in our earlier investigation.This study aimed to evaluate the effects of CCRR on SERCA2a and the associated Ca^(2+)homeostasis in myocardial infarction(MI).Overexpression of CCRR via AAV9-mediated delivery not only partially reversed ischemia-induced contractile dysfunction but also alleviated abnormal Ca^(2+)homeostasis and reduced the heightened methylation level of SERCA2a following MI.These effects were also observed in CCRR overexpressing transgenic mice.A conserved sequence domain of CCRR mimicked the protective function observed with the full length.Furthermore,silencing CCRR in healthy mice led to intracellular Ca^(2+)overloading of cardiomyocytes.CCRR increased SERCA2a protein stability by upregulating FTO expression.The direct interaction between CCRR and FTO protein was characterized by RNA-binding protein immunoprecipitation(RIP)analysis and RNA pulldown experiments.Activation of NFATc3 was identified as an upstream mechanism responsible for CCRR downregulation in MI.This study demonstrates that CCRR is a protective lncRNA that acts by maintaining the function of FTO,thereby reducing the m^(6)A RNA methylation level of SERCA2a,ultimately preserving calcium homeostasis for myocardial contractile function in MI.Therefore,CCRR may be considered a promising therapeutic strategy with a beneficial role in cardiac pathology.

关 键 词：CCRR calcium homeostasis FTO myocardial infarction SERCA2A 

分 类 号：R542.22[医药卫生—心血管疾病]