MicroRNA-214 contributes to Ang II-induced cardiac hypertrophy by targeting SIRT3 to provoke mitochondrial malfunction  

作　　者：Yan-qing Ding Yu-hong Zhang Jing Lu Bai Li Wen-jing Yu Zhong-bao Yue Yue-huai Hu Pan-xia Wang Jing-yan Li Si-dong Cai Jian-tao Ye Pei-qing 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]Guangdong Key Laboratory of Chiral Molecule and Drug Discovery,Sun Yat-Sen University,Guangzhou 510006,China [3]International Institute for Translational Chinese Medicine,School of Pharmaceutical Sciences,Guangzhou University of Chinese Medicine,Guangzhou 510006,China

出　　处：《Acta Pharmacologica Sinica》2021年第9期1422-1436,共15页中国药理学报（英文版）

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

摘　　要：Reduction of expression and activity of sirtuin 3(SIRT3)contributes to the pathogenesis of cardiomyopathy via inducing mitochondrial injury and energy metabolism disorder.However,development of effective ways and agents to modulate SIRT3 remains a big challenge.In this study we explored the upstream suppressor of SIRT3 in angiotensinⅡ(AngⅡ)-induced cardiac hypertrophy in mice.We first found that SIRT3 deficiency exacerbated AngⅡ-induced cardiac hypertrophy,and resulted in the development of spontaneous heart failure.Since miRNAs play crucial roles in the pathogenesis of cardiac hypertrophy,we performed miRNA sequencing on myocardium tissues from AngⅡ-infused Sirt3^(−/−)and wild type mice,and identified microRNA-214(miR-214)was significantly up-regulated in AngⅡ-infused mice.Similar results were also obtained in AngⅡ-treated neonatal mouse cardiomyocytes(NMCMs).Using dual-luciferase reporter assay we demonstrated that SIRT3 was a direct target of miR-214.Overexpression of miR-214 in vitro and in vivo decreased the expression of SIRT3,which resulted in extensive mitochondrial damages,thereby facilitating the onset of hypertrophy.In contrast,knockdown of miR-214 counteracted AngⅡ-induced detrimental effects via restoring SIRT3,and ameliorated mitochondrial morphology and respiratory activity.Collectively,these results demonstrate that miR-214 participates in AngⅡ-induced cardiac hypertrophy by directly suppressing SIRT3,and subsequently leading to mitochondrial malfunction,suggesting the potential of miR-214 as a promising intervention target for antihypertrophic therapy.

关 键 词：cardiac hypertrophy angiotensin II miR-214 SIRT3 mitochondrial malfunction neonatal mouse cardiomyocytes 

分 类 号：R54[医药卫生—心血管疾病]