Inhibition of long noncoding RNA Gm41724 alleviates pressure overload-induced cardiac fibrosis by regulating lamina-associated polypeptide 2α

• Published in: Pharmacological research Vol. 188; p. 106677
• Main Authors: Kong, Qihang, Zhou, Junteng, Ma, Chi, Wei, Zisong, Chen, Yan, Cheng, Yue, Wu, Wenchao, Zhou, Zhichao, Tang, Yong, Liu, Xiaojing
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.02.2023
• Subjects: Cardiac fibroblast activation; Cardiac fibrosis; Cardiomyopathies - metabolism; Fibroblasts - metabolism; Fibrosis; Humans; Long noncoding RNA; Myocardium - pathology; Pressure overload; RNA binding protein; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; Transforming Growth Factor beta1 - metabolism; Cardiac fibroblast activation; Cardiac fibrosis; Pressure overload; Long noncoding RNA; RNA binding protein
• ISSN: 1043-6618; 1096-1186; 1096-1186
• DOI: 10.1016/j.phrs.2023.106677

Cardiac fibrosis is a pathological process underlying myocardial remodeling and is characterized by excessive deposition of the myocardial extracellular matrix. Long noncoding RNAs (lncRNAs) have emerged as critical regulators of various biological processes. In this study, we investigated the role of a novel lncRNA, Gm41724, in cardiac fibrosis induced by pressure overload. High-throughput whole transcriptome sequencing analysis was performed to detect differentially expressed lncRNAs in cardiac fibroblasts (CFs) with or without TGF-β1 treatment. Differential expression analysis and gene set enrichment analysis identified Gm41724 as a potential molecule targeting fibrosis. Gm41724 positively regulated the activation of CFs induced by TGF-β1 and pressure overload. Knocking down Gm41724 could inhibit the differentiation of CFs into myofibroblasts and alleviate cardiac fibrosis induced by pressure overload. Mechanistically, comprehensive identification of RNA-binding proteins by mass spectrometry (CHIRP-MS) and RNA immunoprecipitation (RIP) assay combined with other methods of molecular biological revealed the important role of Gm41724 binding to lamina-associated polypeptide 2α (lap2α) for the activation of CFs. Further mechanistic studies indicated that the regulator of G protein signaling 4 (Rgs4), as the downstream effector of Gm41724/lap2α, regulated CFs activation. Our results implicated the involvement of Gm41724 in cardiac fibrosis induced by pressure overload and it is expected to be a promising target for anti-fibrotic therapy. [Display omitted]