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学科主题: 临床医学
题名:
MicroRNA-221 inhibits autophagy and promotes heart failure by modulating the p27/CDK2/mTOR axis
作者: Su, M.1,2; Wang, J.1,2; Wang, C.1,2; Wang, X.1,2; Dong, W.3,4; Qiu, W.5,6; Wang, Y.1,2; Zhao, X.7; Zou, Y.1,2; Song, L.1,2; Zhang, L.3,4; Hui, R.1,2
刊名: CELL DEATH AND DIFFERENTIATION
发表日期: 2015-06-01
DOI: 10.1038/cdd.2014.187
卷: 22, 期:6, 页:986-999
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Biochemistry & Molecular Biology ; Cell Biology
研究领域[WOS]: Biochemistry & Molecular Biology ; Cell Biology
关键词[WOS]: CARDIAC-HYPERTROPHY ; PROTEIN-KINASE ; HEMODYNAMIC STRESS ; DOWN-REGULATION ; P27 ; PHOSPHORYLATION ; P27(KIP1) ; CARDIOMYOCYTES ; EXPRESSION ; PATHWAY
英文摘要:

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.

语种: 英语
所属项目编号: 2007DFC30340 ; 2010CB732601 ; 2011BAI11B04 ; 81070100 ; 30700322
项目资助者: Ministry of Science and Technology of China ; National Natural Science Foundation of China
WOS记录号: WOS:000353916700011
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/63536
Appears in Collections:北京大学第一临床医学院_泌尿外科_期刊论文

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作者单位: 1.Chinese Acad Med Sci, State Key Lab Cardiovasc Dis, Sino German Lab Mol Med, Fuwai Hosp,Natl Ctr Cardiovasc Dis, Beijing 100037, Peoples R China
2.Peking Union Med Coll, Beijing 100037, Peoples R China
3.Chinese Acad Med Sci, Inst Lab Anim Sci, Key Lab Human Dis Comparat Med, Minist Hlth, Beijing 100021, Peoples R China
4.Peking Union Med Coll, Beijing 100021, Peoples R China
5.Peking Univ, Dept Urol, Hosp 1, Beijing 100034, Peoples R China
6.Inst Urol, Beijing 100034, Peoples R China
7.Qingdao Univ, Qingdao Municipal Hosp, Dept Cardiol, Qingdao 266071, Peoples R China

Recommended Citation:
Su, M.,Wang, J.,Wang, C.,et al. MicroRNA-221 inhibits autophagy and promotes heart failure by modulating the p27/CDK2/mTOR axis[J]. CELL DEATH AND DIFFERENTIATION,2015,22(6):986-999.
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