【摘 要】
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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 c
【机 构】
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Department of Pharmacology and Toxicology,School of Pharmaceutical Sciences,National and Local Unite
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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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