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.
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This research was supported by grants from 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) and the Young Teacher Training Program of Sun Yat-sen University (18ykpy26).
The authors declare no competing interests.
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Ding, Yq., Zhang, Yh., Lu, J. et al. MicroRNA-214 contributes to Ang II-induced cardiac hypertrophy by targeting SIRT3 to provoke mitochondrial malfunction. Acta Pharmacol Sin 42, 1422–1436 (2021). https://doi.org/10.1038/s41401-020-00563-7
- cardiac hypertrophy
- angiotensin II
- mitochondrial malfunction
- neonatal mouse cardiomyocytes