Long Non-Coding RNA 554 Promotes Cardiac Fibrosis via TGF-β1 Pathway in Mice Following Myocardial Infarction.

Bihui Luo,Shijun Huang,Dunzheng Han,Hao Xue,Zhiyu He,Dongfeng Lu,Jinping Wang,Peiying Liu,Xiaojun Zeng

doi:10.3389/fphar.2020.585680

Abstract

Rationale: Cardiac fibrosis is observed in nearly every form of myocardial disease. Long non-coding RNAs (lncRNAs) have been shown to play an important role in cardiac fibrosis, but the detailed molecular mechanism remains unknown. Object: We aimed at characterizing lncRNA 554 expression in murine cardiac fibroblasts (CFs) after myocardial infarction (MI) to identify CF-enriched lncRNA and investigate its function and contribution to cardiac fibrosis and function. Methods and Results: In this study, we identified lncRNA NONMMUT022554 (lncRNA 554) as a regulator of MI-induced cardiac fibrosis. We found that lncRNA 554 was significantly up-regulated in the mouse hearts following MI. Further study showed that lncRNA 554 was predominantly expressed in cardiac fibroblasts, indicating a potential role of lncRNA 554 in cardiac fibrosis. In vitro knockdown of lncRNA 554 by siRNA suppressed fibroblasts migration and expression of extracellular matrix (ECM); while overexpression of lncRNA 554 promoted expression of ECM genes. Consistently, lentivirus mediated in vivo knockdown of lncRNA 554 could inhibit cardiac fibrosis and improve cardiac function in mouse model of MI. More importantly, TGF-β1 inhibitor (TEW-7197) could reverse the pro-fibrotic function of lncRNA 554 in CFs. This suggests that the effects of lncRNA 554 on cardiac fibrosis is TGF-β1 dependent. Conclusion: Collectively, our study illustrated the role of lncRNA 554 in cardiac fibrosis, suggested that lncRNA 554 might be a novel target for cardiac fibrosis.

Highlights

Cardiovascular diseases are the leading cause of death in the world (Gourdie et al, 2016)
To determine the distribution of long noncoding RNAs (lncRNAs) 554 in heart, qRT-PCR was conducted in fibroblasts and cardiomyocytes respectively
Our results showed that lncRNA 554 was enriched in cardiac fibroblasts (CFs) compared to cardiomyocytes (CMs) (Figure 1C), suggesting lncRNA 554 might be an important regulator in cardiac fibrosis

Summary

Introduction

Cardiovascular diseases are the leading cause of death in the world (Gourdie et al, 2016). Cardiac fibrosis is associated with nearly every form of myocardial diseases (Travers et al, 2016). Upon myocardial infarction (MI), cardiac fibroblasts (CFs) begin to activate and remodel myocardium by secreting excessive extracellular matrix (ECM), leading to the stiffness and reduced compliance of heart. Excessive ECM deposition is a main contributor in the progression of heart failure and other forms of cardiac disease (Kong et al, 2014; Travers et al, 2016). TGF-β1 is a central regulator of ECM deposition in injury-induced fibrosis in heart. TGF-β1-mediated ECM synthesis is essential for wound repair, but excess ECM deposition leads to fibrosis (Walton et al, 2017; Xie et al, 2019; Yin et al, 2019). A further characterization of the cellular and molecular mechanisms of cardiac fibrosis is needed to identify specific regulatory molecules and targets

Objectives

Methods

Results

Conclusion