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

Yan-qing Ding1, Yu-hong Zhang1, Jing Lu1, Bai Li2, Wen-jing Yu1, Zhong-bao Yue1, Yue-huai Hu1, Pan-xia Wang1, Jing-yan Li3, Si-dong Cai1, Jian-tao Ye1, Pei-qing Liu1
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
Correspondence to: Jian-tao Ye:, Pei-qing Liu:,
DOI: 10.1038/s41401-020-00563-7
Received: 16 August 2020
Accepted: 21 October 2020
Advance online: 27 November 2020


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 angiotensin II (Ang II)-induced cardiac hypertrophy in mice. We first found that SIRT3 deficiency exacerbated Ang II-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 Ang II-infused Sirt3−/− and wild type mice, and identified microRNA- 214 (miR-214) was significantly up-regulated in Ang II-infused mice. Similar results were also obtained in Ang II-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 Ang II-induced detrimental effects via restoring SIRT3, and ameliorated mitochondrial morphology and respiratory activity. Collectively, these results demonstrate that miR-214 participates in Ang II-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.
Keywords: cardiac hypertrophy; angiotensin II; miR-214; SIRT3; mitochondrial malfunction; neonatal mouse cardiomyocytes

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