PMID- 25394488 OWN - NLM STAT- MEDLINE DCOM- 20151026 LR - 20220318 IS - 1476-5403 (Electronic) IS - 1350-9047 (Print) IS - 1350-9047 (Linking) VI - 22 IP - 6 DP - 2015 Jun TI - MicroRNA-221 inhibits autophagy and promotes heart failure by modulating the p27/CDK2/mTOR axis. PG - 986-99 LID - 10.1038/cdd.2014.187 [doi] AB - 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. FAU - Su, M AU - Su M AD - 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. FAU - Wang, J AU - Wang J AD - 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. FAU - Wang, C AU - Wang C AD - 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. FAU - Wang, X AU - Wang X AD - 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. FAU - Dong, W AU - Dong W AD - 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. FAU - Qiu, W AU - Qiu W AD - Department of Urology, Peking University First Hospital and the Institute of Urology, Beijing 100034, China. FAU - Wang, Y AU - Wang Y AD - 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. FAU - Zhao, X AU - Zhao X AD - Department of Cardiology, Qingdao Municipal Hospital, Qingdao University, Qingdao 266071, China. FAU - Zou, Y AU - Zou Y AD - 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. FAU - Song, L AU - Song L AD - 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. FAU - Zhang, L AU - Zhang L AD - 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. FAU - Hui, R AU - Hui R AD - 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. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20141114 PL - England TA - Cell Death Differ JT - Cell death and differentiation JID - 9437445 RN - 0 (MicroRNAs) RN - 0 (Proliferating Cell Nuclear Antigen) RN - 0 (p27 antigen) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM EIN - Cell Death Differ. 2021 Jan;28(1):420-422. PMID: 32632292 MH - Animals MH - Apoptosis/genetics/*physiology MH - Autophagy/genetics/*physiology MH - Blotting, Western MH - Cells, Cultured MH - Echocardiography MH - Heart Failure/genetics/*metabolism MH - Male MH - Mice MH - MicroRNAs/genetics/*metabolism MH - Microscopy, Electron, Transmission MH - Myocardium/metabolism MH - Proliferating Cell Nuclear Antigen/genetics/*metabolism MH - Rats MH - TOR Serine-Threonine Kinases/genetics/*metabolism PMC - PMC4423182 EDAT- 2014/11/15 06:00 MHDA- 2015/10/27 06:00 PMCR- 2016/06/01 CRDT- 2014/11/15 06:00 PHST- 2014/03/14 00:00 [received] PHST- 2014/08/20 00:00 [revised] PHST- 2014/10/09 00:00 [accepted] PHST- 2014/11/15 06:00 [entrez] PHST- 2014/11/15 06:00 [pubmed] PHST- 2015/10/27 06:00 [medline] PHST- 2016/06/01 00:00 [pmc-release] AID - cdd2014187 [pii] AID - 10.1038/cdd.2014.187 [doi] PST - ppublish SO - Cell Death Differ. 2015 Jun;22(6):986-99. doi: 10.1038/cdd.2014.187. Epub 2014 Nov 14.