miR-199a impairs autophagy and induces cardiac hypertrophy through mTOR activation

Basal autophagy is tightly regulated by transcriptional and epigenetic factors to maintain cellular homeostasis. Dysregulation of cardiac autophagy is associated with heart diseases, including cardiac hypertrophy, but the mechanism governing cardiac autophagy is rarely identified. To analyze the in...

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Bibliographic Details
Published in:Cell death and differentiation 2017-07, Vol.24 (7), p.1205-1213
Main Authors: Li, Z, Song, Y, Liu, L, Hou, N, An, X, Zhan, D, Li, Y, Zhou, L, Li, P, Yu, L, Xia, J, Zhang, Y, Wang, J, Yang, X
Format: Article
Language:English
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Activation
Apoptosis
Autophagy
Biochemistry
Biomedical and Life Sciences
Cardiomyocytes
Cell Biology
Cell Cycle Analysis
Coronary artery disease
Eutrophication
Glycogen
Glycogen synthase kinase 3
Heart diseases
Homeostasis
Hypertrophy
Kinases
Life Sciences
Original Paper
Phagocytosis
Rapamycin
Rodents
Stem Cells
TOR protein
Transcription factors
Transgenic animals
Transgenic mice
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Summary:Basal autophagy is tightly regulated by transcriptional and epigenetic factors to maintain cellular homeostasis. Dysregulation of cardiac autophagy is associated with heart diseases, including cardiac hypertrophy, but the mechanism governing cardiac autophagy is rarely identified. To analyze the in vivo function of miR-199a in cardiac autophagy and cardiac hypertrophy, we generated cardiac-specific miR-199a transgenic mice and showed that overexpression of miR-199a was sufficient to inhibit cardiomyocyte autophagy and induce cardiac hypertrophy in vivo . miR-199a impaired cardiomyocyte autophagy in a cell-autonomous manner by targeting glycogen synthase kinase 3 β (GSK3 β )/mammalian target of rapamycin (mTOR) complex signaling. Overexpression of autophagy related gene 5 (Atg5) attenuated the hypertrophic effects of miR-199a overexpression on cardiomyocytes, and activation of autophagy using rapamycin was sufficient to restore cardiac autophagy and decrease cardiac hypertrophy in miR-199a transgenic mice. These results reveal a novel role of miR-199a as a key regulator of cardiac autophagy, suggesting that targeting miRNAs controlling autophagy as a potential therapeutic strategy for cardiac disease.
ISSN:1350-9047
1476-5403
DOI:10.1038/cdd.2015.95