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MicroRNA302-367-PI3K-PTEN-AKT-mTORC1 pathway promotes the development of cardiac hypertrophy through controlling autophagy

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Abstract

Cardiac hypertrophy at a decompensated state eventually leads to heart failure that mostly contributes to deaths globally. Dysregulated cardiac autophagy is a hallmark of a diseased heart, and a close contact between cardiac autophagy and cardiac hypertrophy is emerging. MicroRNAs (miRNAs) have been recently reported to be prominently implicated in cardiac hypertrophy through regulating cardiac autophagy. However, the role and function of miR302–367 clusters in cardiac autophagy and cardiac hypertrophy remain largely masked. Therefore, to investigate the performance of miR302–367 in cardiac hypertrophy, the specific in vitro hypertrophic model was established in H9c2 cells upon Ang II treatment. Consequently, we discovered a distinct inhibition on autophagy and a remarkable upregulation of miR302–367 expression in hypertrophic H9c2 cells. Besides, loss- and gain-of-function assays demonstrated miR302–367 inhibited autophagy and then aggravated cardiac hypertrophy. Mechanically, PTEN was predicted and confirmed as the shared target of miR302–367. Further, we recognized the apparent inactivation of PI3K/AKT/mTORC1 signaling in the face of miR302–367 suppression in Ang II-induced hypertrophic H9c2 cells. Moreover, co-treatment of PTEN inhibitor re-activated the PI3K/AKT/mTORC1 pathway, therefore counteracting the pro-autophagic and anti-hypertrophic effects of miR302–367 depletion on cardiomyocytes. These findings unveiled the pivotal role of the miR302–367 cluster in regulating cardiac autophagy and therefore modulating cardiac hypertrophy through PTEN/PI3K/AKT/mTORC1 signaling, indicating a promising therapeutic strategy for cardiac hypertrophy and even heart failure.

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Acknowledgments

Thanks to all those who participated in this study.

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Authors and Affiliations

  1. Cardiology Department of Pediatric of the First Hospital of Jilin University, No.71 Xinmin Street, Changchun City, 130021, Jilin Province, China

    Lianhua Jin, Yan Zhou, Lizhi Han & Jinhua Piao

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  1. Lianhua Jin
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Correspondence to Jinhua Piao.

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Electronic Supplementary Material

Supplementary Figure 1

Enhanced expression of miR302–367 on the autophagic and hypertrophic phenotypes in H9c2 cells. (A-B) qRT-PCR analysis of miR302–367 cluster (A) and autophagy-related genes (B) in H9c2 cells. (C) Western blot analysis of autophagy-related proteins in H9c2 cells under miR302–367 mimics. (D) Images of autophagosomes in indicated H9c2 cells were obtained under electron microscopy (Olympus). (E) The levels of hypertrophic markers in H9c2 cells with or without miR302–367 upregulation were evaluated via qRT-PCR. (F) IF staining of the surface area of H9c2 cells under miR302–367 upregulation. **P < 0.01. (PNG 688 kb)

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Jin, L., Zhou, Y., Han, L. et al. MicroRNA302-367-PI3K-PTEN-AKT-mTORC1 pathway promotes the development of cardiac hypertrophy through controlling autophagy. In Vitro Cell.Dev.Biol.-Animal 56, 112–119 (2020). https://doi.org/10.1007/s11626-019-00417-5

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