3' untranslated region of Ckip-1 inhibits cardiac hypertrophy independently of its cognate protein.

European heart journal 2021 Sep 21

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3' untranslated region (3' UTR) of mRNA is more conserved than other non-coding sequences in vertebrate genomes, and its sequence space has substantially expanded during the evolution of higher organisms, which substantiates their significance in biological regulation. However, the independent role of 3' UTR in cardiovascular disease was largely unknown. Using bioinformatics, RNA fluorescent in situ hybridization and quantitative real-time polymerase chain reaction, we found that 3' UTR and coding sequence regions of Ckip-1 mRNA exhibited diverse expression and localization in cardiomyocytes. We generated cardiac-specific Ckip-1 3' UTR overexpression mice under wild type and casein kinase 2 interacting protein-1 (CKIP-1) knockout background. Cardiac remodelling was assessed by histological, echocardiography, and molecular analyses at 4 weeks after transverse aortic constriction (TAC) surgery. The results showed that cardiac Ckip-1 3' UTR significantly inhibited TAC-induced cardiac hypertrophy independent of CKIP-1 protein. To determine the mechanism of Ckip-1 3' UTR in cardiac hypertrophy, we performed transcriptome and metabolomics analyses, RNA immunoprecipitation, biotin-based RNA pull-down, and reporter gene assays. We found that Ckip-1 3' UTR promoted fatty acid metabolism through AMPK-PPARα-CPT1b axis, leading to its protection against pathological cardiac hypertrophy. Moreover, Ckip-1 3' UTR RNA therapy using adeno-associated virus obviously alleviates cardiac hypertrophy and improves heart function. These findings disclose that Ckip-1 3' UTR inhibits cardiac hypertrophy independently of its cognate protein. Ckip-1 3' UTR is an effective RNA-based therapy tool for treating cardiac hypertrophy and heart failure. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

Citation

Yinlong Zhao, Shukuan Ling, Jianwei Li, Guohui Zhong, Ruikai Du, Youyou Li, Yanqing Wang, Caizhi Liu, Xiaoyan Jin, Wei Liu, Tong Liu, Yuheng Li, Dingsheng Zhao, Weijia Sun, Zizhong Liu, Zifan Liu, Junjie Pan, Xinxin Yuan, Xingcheng Gao, Wenjuan Xing, Yan-Zhong Chang, Yingxian Li. 3' untranslated region of Ckip-1 inhibits cardiac hypertrophy independently of its cognate protein. European heart journal. 2021 Sep 21;42(36):3786-3799