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Nat Commun. 2018 Feb 16;9(1):700. doi: 10.1038/s41467-018-03019-z.

Loss of microRNA-128 promotes cardiomyocyte proliferation and heart regeneration.

Author information

1
Key Laboratory of Molecular Target and Clinical Pharmacology, School of Pharmaceutical Sciences & Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 511436, China.
2
Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA.
3
Department of Molecular Biology, Radboud Institute of Molecular Life Sciences and Faculty of Science, Radboud University, Nijmegen, 6525, Gelderland, The Netherlands.
4
Samaritan Medical Center, 830 Washington Street, Watertown, NY, 13601, USA.
5
College of Engineering and Applied Science, University of Cincinnati, Cincinnati, OH, 45221, USA.
6
Division of Liver Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510630, China.
7
Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA.
8
Division of Cardiovascular Health and Disease, Department of Internal Medicine, Heart, Lung and Vascular Institute, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA.
9
Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA.
10
Key Laboratory of Molecular Target and Clinical Pharmacology, School of Pharmaceutical Sciences & Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 511436, China. yuxycn@aliyun.com.
11
Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA. yi-gang.wang@uc.edu.

Abstract

The goal of replenishing the cardiomyocyte (CM) population using regenerative therapies following myocardial infarction (MI) is hampered by the limited regeneration capacity of adult CMs, partially due to their withdrawal from the cell cycle. Here, we show that microRNA-128 (miR-128) is upregulated in CMs during the postnatal switch from proliferation to terminal differentiation. In neonatal mice, cardiac-specific overexpression of miR-128 impairs CM proliferation and cardiac function, while miR-128 deletion extends proliferation of postnatal CMs by enhancing expression of the chromatin modifier SUZ12, which suppresses p27 (cyclin-dependent kinase inhibitor) expression and activates the positive cell cycle regulators Cyclin E and CDK2. Furthermore, deletion of miR-128 promotes cell cycle re-entry of adult CMs, thereby reducing the levels of fibrosis, and attenuating cardiac dysfunction in response to MI. These results suggest that miR-128 serves as a critical regulator of endogenous CM proliferation, and might be a novel therapeutic target for heart repair.

PMID:
29453456
PMCID:
PMC5816015
DOI:
10.1038/s41467-018-03019-z
[Indexed for MEDLINE]
Free PMC Article

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