MicroRNA-221 inhibits autophagy and promotes heart failure by modulating the p27/CDK2/mTOR axis

• Published in: Cell death and differentiation Vol. 22; no. 6; pp. 986 - 999
• Main Authors: Su, M, Wang, J, Wang, C, Wang, X, Dong, W, Qiu, W, Wang, Y, Zhao, X, Zou, Y, Song, L, Zhang, L, Hui, R
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-06-2015; Nature Publishing Group
• Subjects: 13/109; 13/2; 13/95; 14/19; 14/28; 38/77; 38/89; 42/44; 59; 631/80/39/2346; 64/60; 96/63; Animals; Apoptosis; Apoptosis - genetics; Apoptosis - physiology; Autophagy; Autophagy - genetics; Autophagy - physiology; Biochemistry; Biomedical and Life Sciences; Blotting, Western; Cardiomyocytes; Cardiovascular diseases; Cell Biology; Cell Cycle Analysis; Cells, Cultured; Congestive heart failure; Cyclin-dependent kinase 2; Cyclin-dependent kinase inhibitor p27; Cyclin-dependent kinases; Echocardiography; Enzyme inhibitors; Heart failure; Heart Failure - genetics; Heart Failure - metabolism; Homeostasis; Hypertrophy; Kinases; Life Sciences; Male; Mice; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; Microscopy, Electron, Transmission; Microtubule-associated protein 1; miRNA; Myocardium - metabolism; Original Paper; Phagocytosis; Proliferating Cell Nuclear Antigen - genetics; Proliferating Cell Nuclear Antigen - metabolism; Rapamycin; Rats; siRNA; Stem Cells; TOR protein; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism; Transgenic mice
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2014.187

MicroRNAs have emerged as crucial regulators of cardiac homeostasis and remodeling in various cardiovascular diseases. We previously demonstrated that miR-221 regulated cardiac hypertrophy
in vitro
. In the present study, we demonstrated that the cardiac-specific overexpression of miR-221 in mice evoked cardiac dysfunction and heart failure. The lipidated form of microtubule-associated protein 1 light chain 3 was significantly decreased and sequestosome 1 was accumulated in cardiac tissues of transgenic (TG) mice, indicating that autophagy was impaired. Overexpression of miR-221
in vitro
reduced autophagic flux through inhibiting autophagic vesicle formation. Furthermore, mammalian target of rapamycin (mTOR) was activated by miR-221, both
in vivo
and
in vitro
. The inactivation of mTOR abolished the miR-221-induced inhibition of autophagy and cardiac remodeling. Our previous study has demonstrated that cyclin-dependent kinase (CDK) inhibitor p27 was a direct target of miR-221 in cardiomyocytes. Consistently, the expression of p27 was markedly suppressed in the myocardia of TG mice. Knockdown of p27 by siRNAs was sufficient to mimic the effects of miR-221 overexpression on mTOR activation and autophagy inhibition, whereas overexpression of p27 rescued miR-221-induced autophagic flux impairment. Inhibition of CDK2 restored the impaired autophagic flux and rescued the cardiac remodeling induced by either p27 knockdown or miR-221 overexpression. These findings reveal that miR-221 is an important regulator of autophagy balance and cardiac remodeling by modulating the p27/CDK2/mTOR axis, and implicate miR-221 as a therapeutic target in heart failure.