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Long noncoding RNA Cfast regulates cardiac fibrosis

Authors :
Feng Zhang
Xuyang Fu
Masaharu Kataoka
Ning Liu
Yingchao Wang
Feng Gao
Tian Liang
Xiaoxuan Dong
Jianqiu Pei
Xiaoyun Hu
Wei Zhu
Hong Yu
Douglas B. Cowan
Xinyang Hu
Zhan-Peng Huang
Jian’an Wang
Da-Zhi Wang
Jinghai Chen
Source :
Molecular Therapy: Nucleic Acids, Vol 23, Iss , Pp 377-392 (2021)
Publication Year :
2021
Publisher :
Elsevier, 2021.

Abstract

Cardiac fibrosis occurs in most cardiac diseases, which reduces cardiac muscle compliance, impairs both systolic and diastolic heart function and, ultimately, leads to heart failure. Long noncoding RNAs (lncRNAs) have recently emerged as important regulators of a variety of biological processes; however, little is known about the expression and function of lncRNAs in cardiac fibrosis. Using unbiased transcriptome profiling in a mouse model of myocardial infarction (MI), we identified a cardiac fibroblast-enriched lncRNA (AK048087) named cardiac fibroblast-associated transcript (Cfast), which is significantly elevated after MI. Silencing Cfast expression by small interfering RNAs (siRNAs) or lentiviral short hairpin RNAs (shRNAs) resulted in suppression of fibrosis-related gene expression and transdifferentiation of myofibroblasts into cardiac fibroblasts. Depletion of Cfast by lentiviral shRNAs in mouse hearts significantly attenuated cardiac fibrosis induced by MI or isoproterenol-infusion. Importantly, inhibition of Cfast ameliorated cardiac function following cardiac injury. RNA pull-down followed by mass spectrometry analyses identified COTL1 (coactosin-like 1) as one of the Cfast interacting proteins. Mechanistically, Cfast competitively inhibits the COTL1 interaction with TRAP1 (transforming growth factor-β receptor-associated protein 1), which enhances TGF-β signaling by augmenting SMAD2/SMAD4 complex formation. Therefore, our study identifies Cfast as a novel cardiac fibroblast-enriched lncRNA that regulates cardiac fibroblast activation in response to pathophysiological stress. Cfast could serve as a potential therapeutic target for the prevention of cardiac fibrosis and cardiac diseases.

Details

Language :
English
ISSN :
21622531
Volume :
23
Issue :
377-392
Database :
Directory of Open Access Journals
Journal :
Molecular Therapy: Nucleic Acids
Publication Type :
Academic Journal
Accession number :
edsdoj.0a9c8e4ee8de4afbbf0681ffa82e49d2
Document Type :
article
Full Text :
https://doi.org/10.1016/j.omtn.2020.11.013