MicroRNA-34c-5p provokes isoprenaline-induced cardiac hypertrophy by modulating autophagy via targeting ATG4B  

作　　者：Yuhong Zhang Yanqing Ding Min Li Jing Yuan Youhui Yu Xueying Bi Huiqi Hong Jiantao Ye Peiqing Liu 

机构地区：[1]Department of Pharmacology and Toxicology,School of Pharmaceutical Sciences,National and Local United Engineering Lab of Druggability and New Drugs Evaluation,Sun Yat-sen University,Guangzhou 510006,China [2]State Key Laboratory of Oncology in Southern China,Collaborative Innovation Center for Cancer Medicine,Sun Yat-sen University Cancer Center,Guangzhou 510006,China

出　　处：《Acta Pharmaceutica Sinica B》2022年第5期2374-2390,共17页药学学报（英文版）

基　　金：supported by grants from the National Natural Science Foundation of China (81872860,81673433,and82070268);Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program (2017BT01Y093,China);National Major Special Projects for the Creation and Manufacture of New Drugs (2019ZX09301104,China);National Engineering and Technology Research Center for New drug Druggability Evaluation (Seed Program of Guangdong Province,2017B090903004,China);Special Program for Applied Science and Technology of Guangdong Province (2015B020232009,China);Guangdong Basic and Applied Basic Research Foundation(2020A1515011512,China);Young Teacher Training Program of Sun Yat-sen University (18ykpy26,China)。

摘　　要：Pathological cardiac hypertrophy serves as a significant foundation for cardiac dysfunction and heart failure. Recently, growing evidence has revealed that microRNAs(miRNAs) play multiple roles in biological processes and participate in cardiovascular diseases. In the present research, we investigate the impact of miRNA-34 c-5 p on cardiac hypertrophy and the mechanism involved. The expression of miR-34 c-5 p was proved to be elevated in heart tissues from isoprenaline(ISO)-infused mice. ISO also promoted miR-34 c-5 p level in primary cultures of neonatal rat cardiomyocytes(NRCMs). Transfection with miR-34 c-5 p mimic enhanced cell surface area and expression levels of foetal-type genes atrial natriuretic factor(Anf) and β-myosin heavy chain(β-Mhc) in NRCMs. In contrast, treatment with miR-34 c-5 p inhibitor attenuated ISO-induced hypertrophic responses. Enforced expression of miR-34 c-5 p by tail intravenous injection of its agomir led to cardiac dysfunction and hypertrophy in mice, whereas inhibiting miR-34 c-5 p by specific antagomir could protect the animals against ISO-triggered hypertrophic abnormalities. Mechanistically, miR-34 c-5 p suppressed autophagic flux in cardiomyocytes, which contributed to the development of hypertrophy. Furthermore, the autophagy-related gene 4 B(ATG4 B) was identified as a direct target of miR-34 c-5 p, and miR-34 c-5 p was certified to interact with 3’untranslated region of Atg4 b mRNA by dual-luciferase reporter assay. miR-34 c-5 p reduced the expression of ATG4 B, thereby resulting in decreased autophagy activity and induction of hypertrophy. Inhibition of miR-34 c-5 p abolished the detrimental effects of ISO by restoring ATG4 B and increasing autophagy. In conclusion, our findings illuminate that miR-34 c-5 p participates in ISO-induced cardiac hypertrophy, at least partly through suppressing ATG4 B and autophagy. It suggests that regulation of miR-34 c-5 p may offer a new way for handling hypertrophy-related cardiac dysfunction.

关 键 词：Pathological cardiac hypertrophy ISOPRENALINE miR-34c-5p ATG4B LC3 AUTOPHAGY Autophagic flux Neonatal rat cardiomyocytes Mice 

分 类 号：R541[医药卫生—心血管疾病]