Cardiac-Specific Overexpression of miR-222 Induces Heart Failure and Inhibits Autophagy in Mice.
BACKGROUND
MicroRNAs play a crucial role in the regulation of pathological cardiac remodeling and heart failure. Previously, we found that overexpression of miR-221 induces heart failure in mice. The miR-222 and miR-221 share the same gene cluster, however, the role of miR-222 in the regulation of cardiac function remained ill-defined.


RESULTS
Transgenic mice with cardiac-specific expression of miR-222 (Tg-miR-222) mice were generated. The Tg-miR-222 mice developed significantly enlarged hearts at 4 weeks of age. Transthoracic echocardiograph data indicated that the hearts of Tg-miR-222 mice exhibited an increased left ventricular end-diastolic internal diameter and decreased fractional shortening. We observed that the LC3-II in Tg-miR-222 mice was decreased accompanied with the upregulation of p62, indicating the autophagy inhibition in the hearts of Tg-miR-222 mice. The mTOR pathway, a negative regulator of autophagy, was activated in the hearts of Tg-miR-222 mice. The expression of p27 was downregulated by miR-222 overexpression.


CONCLUSIONS
Our data indicate that miR-222 overexpression induces heart failure in mice. The downregulation of p27 and the activation of mTOR pathway may be involved in miR-222-induced heart failure and autophagy inhibition. Thus, targeting miR-222 expression may be a therapeutic strategy against pathological cardiac remodeling.
State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Ming
M
Su
Zhiguo
Z
Chen
Changxin
C
Wang
Lei
L
Song
Yubao
Y
Zou
Lianfeng
L
Zhang
Rutai
R
Hui
Jizheng
J
Wang
D000818:Animals; D001343:Autophagy / Q000235:genetics*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics* / Q000378:metabolism; D004452:Echocardiography; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D061251:Primary Cell Culture; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D051758:Transcription Factor TFIIH; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
C490981:Gtf2h1 protein, mouse; C546123:MIRN222 microRNA, mouse; C480860:Map1lc3b protein, mouse; D035683:MicroRNAs; D008869:Microtubule-Associated Proteins; D014157:Transcription Factors; D050760:Cyclin-Dependent Kinase Inhibitor p27; D051758:Transcription Factor TFIIH; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases