MicroRNA-20b Promotes Cardiac Hypertrophy by the Inhibition of Mitofusin 2-Mediated Inter-organelle Ca2+ Cross-Talk

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  • Author: Yue Qiu, Rongchao Cheng, Chaoqi Liang, Yuan Yao, Wenhao Zhang, Jie Zhang, Mingyu Zhang, Baiyan Li, Chaoqian Xu,and Rong Zhang
  • Journal: Mol Ther Nucleic Acids
  • Doi: https://www.doi.org/10.1016/j.omtn.2020.01.017
  • Publication Date: 2020 Jan 23

Products/Services used in the paper

Quotation shows PackGene:rAAV was used as carrier, among which rAAV9 is the most efficient vector for myocardial transduction. For this regard, rAAV9-antimiR- 20b or rAAV9-NC was produced (PackGene Biotech) and the sequences were delivered into mouse, respectively, through tail vein injection at 1 x 10^11 vg (viral genomes) per animal at 5 weeks before TAC.

Research Field:heart

Targeted organ:heart

Animal or cell line strain:Adult male Kunming mice (weight 22–25 g)

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Abstract

MicroRNA (miRNA) and mitofusin-2 (Mfn2) are important in the development of cardiac hypertrophy, but the target relationship and mechanism associated with Ca2+ handling between SR and mitochondria under hypertrophic condition is not established. Mfn2 expression, Mfn2-mediated interorganelle Ca2+ cross-talk, and target regulation by miRNA-20b (miR-20b) were evaluated using animal/cellular hypertrophic models with state-of-the-art techniques. The results demonstrated that Mfn2 was downregulated and miR-20b was upregulated upon the target binding profile under hypertrophic condition. Our data showed that miR-20b induced cardiac hypertrophy that was reversed by recombinant adeno-associated virus vector 9 (rAAV9)-anti-miR-20b or miR-20b antisense inhibitor (AMO-20b). The deleterious action of miR-20b on Mfn2 expression/function and mitochondrial ATP synthesis was observed and reversed by rAAV9-anti-miR-20b or AMO-20b. The targeted regulation of miR-20b on Mfn2 was confirmed by luciferase reporter and miRNA-masking. Importantly, the facts that mitochondrial calcium uniporter (MCU) activation by Spermine increased the cytosolic Ca2+ into mitochondria, manifested as enhanced histamine-mediated Ca2+ release from mitochondrial, suggesting that Ca2+ reuptake/buffering capability of mitochondria to cytosolic Ca2+ is injured by miR-20b-mediated Mfn2 signaling, by which leads cytosolic Ca2+ overload and cardiac hypertrophy through Ca2+ signaling pathway. In conclusion, pro-hypertonic miR-20b plays crucial roles in cardiac hypertrophy through downregulation of Mfn2 and cytosolic Ca2+ overload by weakening the buffering capability of mitochondria.

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