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Cardiovasc Res. 2016 Nov 1;112(2):543-554. doi: 10.1093/cvr/cvw201.

Long non-coding RNAs link extracellular matrix gene expression to ischemic cardiomyopathy.

Author information

1
Department of Cardiology, Boston Children's Hospital, Harvard Medical School, 320 Longwood Avenue, Boston, MA 02115, USA.
2
The Institute for Translational Medicine and Therapeutics, The Affiliated Zhongshan Hospital of Dalian University, 6 Jiefang Street, Zhongshan District, Dalian 116001, China.
3
Department of Cardiology, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310009, China.
4
Institute of Translational Medicine, Zhejiang University, Hangzhou 310029, China.
5
Department of Cardiology, Keio University School of Medicine, Tokyo, Japan.
6
RNA Information Center, Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory for Biocontrol, Sun Yat-sen University, Guangzhou 510275, PR China.
7
Division of Cardiovascular Medicine, Department of Internal Medicine.
8
Division of Cardiothoracic Surgery, Department of Surgery, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
9
Faculty of Pharmacy, Comenius University, Bratislava, Slovak Republic.
10
Muscle Research Unit, Bosch Institute, The University of Sydney, Sydney, NSW, Australia.
11
Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.

Abstract

Aims:

Ischemic cardiomyopathy (ICM) resulting from myocardial infarction is a major cause of heart failure (HF). Recently, thousands of long non-coding RNAs (lncRNAs) have been discovered and implicated in a variety of biological processes. However, the role of most lncRNAs in HF remains largely unknown. The aim of this study is to test the hypothesis that the expression and function of lncRNAs are differentially regulated in diseased hearts.

Methods and results:

In this study, we performed RNA deep sequencing of protein-coding and non-coding RNAs from cardiac samples of patients with ICM ( n  = 15) and controls ( n  = 15). Genome-wide transcriptome analysis confirmed that many protein-coding genes previously known to be involved in HF were altered in ICM hearts. Among the 145 differentially expressed lncRNAs identified in ICM hearts, we found a set of 35 lncRNAs that display strong positive expression correlation. Expression correlation coefficient analyses of differentially expressed lncRNAs and protein-coding genes revealed a strong association between lncRNAs and extracellular matrix (ECM) protein-coding genes. We overexpressed or knocked down selected lncRNAs in cardiac fibroblasts and our results suggest that lncRNAs are important regulators of fibrosis and the expression of ECM synthesis genes. Moreover, we show that lncRNAs participate in the TGF-β pathway to modulate the expression of ECM genes and myofibroblast differentiation.

Conclusion:

Our studies demonstrate that the expression of many lncRNAs is dynamically regulated in ICM. lncRNAs regulate the expression and function of ECM and cardiac fibrosis during the development of ICM. Our results further indicate that lncRNAs may represent novel regulators of heart function and cardiac disorders, including ICM.

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