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

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.

Dynamic Patterns of N6‐Methyladenosine Profiles of Messenger RNA Correlated with the Cardiomyocyte Regenerability during the Early Heart Development in Mice

“…It is the terminal differentiation and nonrenewability of myocardial tissue in adulthood that prevent the heart from proliferating and repairing itself after the heart injuries, such as ischemia reperfusion injury (IRI) and MI [10][11][12][13][14]. The response of the mammalian heart to MI and the concomitant cell death is the substitution of fibroblasts, extracellular matrix reticulum, and proliferating cells for the damaged myocardium, thereby the scar-forming, called ventricular remodeling [46,47]. Extensive cell therapy studies have used embryonic stem cells (ESC) and induced pluripotent stem cells (iPSC) as exogenous sources of new cardiomyocytes for treatment [9,48].…”

The Roles of lncRNA in Myocardial Infarction: Molecular Mechanisms, Diagnosis Biomarkers, and Therapeutic Perspectives

“…TGF-β1 inhibitor (TEW-7197) could significantly inhibit the fibrosis-promoting function of lncRNA 554 in CFs. These results indicated that the effect of lncRNA 554 on MI-induced myocardial fibrosis was dependent on the TGF-β1 signaling pathway ( Luo et al, 2020 ). Wisper (WISP2 super enhancement factor associated RNA) is a myocardial fibroblast enriched lncRNA that regulates myocardial fibrosis.…”

TGF-β/Smad Signaling Pathway in Tubulointerstitial Fibrosis

“…Long non-coding RNAs (lncRNAs) are an emerging class of non-coding RNAs, which are more than 200 nucleotides in length ( Luo et al, 2020 ; Wang et al, 2021b ). lncRNAs can regulate various biological functions at epigenetic, transcriptional and post-transcriptional levels ( Huang, 2018 ) and bind DNA, RNA and protein ( Wang Y.-N. et al, 2021 ).…”