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.

Details

Title
Loss of microRNA-128 promotes cardiomyocyte proliferation and heart regeneration
Author
Huang, Wei 1 ; Feng, Yuliang 2 ; Liang, Jialiang 3 ; Yu, Hao 3 ; Wang, Cheng 4 ; Wang, Boyu 5 ; Wang, Mingyang 6 ; Jiang, Lin 3 ; Meng, Wei 7 ; Cai, Wenfeng 3 ; Medvedovic, Mario 8 ; Chen, Jenny 8 ; Christian, Paul 3 ; Davidson, W Sean 3 ; Sakthivel Sadayappan 9   VIAFID ORCID Logo  ; Stambrook, Peter J 10 ; Xi-Yong, Yu 2   VIAFID ORCID Logo  ; Wang, Yigang 3 

1  Key Laboratory of Molecular Target and Clinical Pharmacology, School of Pharmaceutical Sciences & Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China; Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA 
2  Key Laboratory of Molecular Target and Clinical Pharmacology, School of Pharmaceutical Sciences & Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China 
3  Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA 
4  Department of Molecular Biology, Radboud Institute of Molecular Life Sciences and Faculty of Science, Radboud University, Nijmegen, Gelderland, The Netherlands 
5  Samaritan Medical Center, Watertown, NY, USA 
6  College of Engineering and Applied Science, University of Cincinnati, Cincinnati, OH, USA 
7  Division of Liver Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China 
8  Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH, USA 
9  Division of Cardiovascular Health and Disease, Department of Internal Medicine, Heart, Lung and Vascular Institute, University of Cincinnati College of Medicine, Cincinnati, OH, USA 
10  Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA 
Pages
1-16
Publication year
2018
Publication date
Feb 2018
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-018-03019-z
ProQuest document ID
2002649834
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.