MicroRNA-221 inhibits autophagy and promotes heart failure by modulating the p27/CDK2/mTOR axis.
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.
State Key Laboratory of Cardiovascular Disease, Sino-German Laboratory for Molecular Medicine, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China.
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M
Su
State Key Laboratory of Cardiovascular Disease, Sino-German Laboratory for Molecular Medicine, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China.
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J
Wang
State Key Laboratory of Cardiovascular Disease, Sino-German Laboratory for Molecular Medicine, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China.
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C
Wang
State Key Laboratory of Cardiovascular Disease, Sino-German Laboratory for Molecular Medicine, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China.
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Wang
Key Laboratory of Human Diseases Comparative Medicine, Ministry of Health, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
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W
Dong
Department of Urology, Peking University First Hospital and the Institute of Urology, Beijing 100034, China.
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W
Qiu
State Key Laboratory of Cardiovascular Disease, Sino-German Laboratory for Molecular Medicine, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China.
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Y
Wang
Department of Cardiology, Qingdao Municipal Hospital, Qingdao University, Qingdao 266071, China.
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X
Zhao
State Key Laboratory of Cardiovascular Disease, Sino-German Laboratory for Molecular Medicine, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China.
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Y
Zou
State Key Laboratory of Cardiovascular Disease, Sino-German Laboratory for Molecular Medicine, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China.
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L
Song
Key Laboratory of Human Diseases Comparative Medicine, Ministry of Health, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
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L
Zhang
State Key Laboratory of Cardiovascular Disease, Sino-German Laboratory for Molecular Medicine, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China.
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R
Hui
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D015153:Blotting, Western; D002478:Cells, Cultured; D004452:Echocardiography; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D046529:Microscopy, Electron, Transmission; D009206:Myocardium / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
D035683:MicroRNAs; D018809:Proliferating Cell Nuclear Antigen; C413374:p27 antigen; D058570:TOR Serine-Threonine Kinases