2. Academic Validation
  3. LncRNA CCRR maintains Ca2+ homeostasis against myocardial infarction through the FTO-SERCA2a pathway

LncRNA CCRR maintains Ca2+ homeostasis against myocardial infarction through the FTO-SERCA2a pathway

  • Sci China Life Sci. 2024 May 16. doi: 10.1007/s11427-023-2527-5.
Hua Yang # 1,  Lina Xuan # 1,  Shengjie Wang 1,  Huishan Luo 1,  Xiaomeng Duan 1,  Jianjun Guo 1,  Shijia Cui 1,  Jieru Xin 1,  Junwei Hao 1,  Xiufang Li 1,  Jun Chen 1,  Feihan Sun 1,  Xiaolin Hu 1,  Siyun Li 1,  Ying Zhang 1,  Lei Jiao 1,  Baofeng Yang 2,  Lihua Sun 3
Affiliations

Affiliations

  • 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.
  • 2 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. yangbf@ems.hrbmu.edu.cn.
  • 3 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. sunlihua0219@163.com.
  • # Contributed equally.
PMID: 38761356 DOI: 10.1007/s11427-023-2527-5
Abstract

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 CA2+ homeostasis in myocardial infarction (MI). Overexpression of CCRR via AAV9-mediated delivery not only partially reversed ischemia-induced contractile dysfunction but also alleviated abnormal CA2+ homeostasis and reduced the heightened methylation level of SERCA2a following MI. These effects were also observed in CCRR over-expressing 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 CA2+ 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 m6A 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.

Keywords

CCRR; FTO; SERCA2a; calcium homeostasis; myocardial infarction.

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