Exosomes Containing LINC00636 Inhibit MAPK1 through the miR-450a-2-3p Overexpression in Human Pericardial Fluid and Improve Cardiac Fibrosis in Patients with Atrial Fibrillation

Abstract

The purpose of this study was to investigate the regulatory mechanism of miR-450a-2-3p in myocardial fibrosis in patients with atrial fibrillation. For this purpose, the expression profile of GSE55296 was extracted from the GEO database, and differentially expressed lncRNAs were identified. Gene ontology analysis of the target genes of mir-450a-2-3p indicated that there was a regulatory relationship between LINC00636 and miR-450a-2-3p. Further, the expression levels of the analyzed RNAs were confirmed by RT-qPCR. TGF-β1-induced cardiac fibroblasts (CFs) and human umbilical vein endothelial cells (HUVECs) were used to establish a myocardial fibrosis model and endothelium-mesenchymal transformation (EMT) model in vivo. We hypothesized that exosomes containing LINC00636 regulate the expression of miR-450a-2-3p. LINC00636 was positively correlated with the expression of miR-450a-2-3p. The overexpression of miR-450a-2-3p suppressed the MAPK1 expression in CFs, thereby inhibiting the expression of α-SMA, COL1, and COL3 and preventing CF proliferation. In HUVECs, the miR-450a-2-3p overexpression upregulated the expression of VE-Cadherin (VE-Cad) and platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31) by inhibiting the mitogen-activated protein kinase 1 (MAPK1) expression, whereas the expression levels of vimentin, COL1, and COL3 decreased. These results indicate that LINC00636, which is present in human pericardial fluid, is an antifibrotic molecule that inhibits MAPK1 through the miR-450a-2-3p overexpression and improves cardiac fibrosis in patients with atrial fibrillation.

Elucidating the mechanism of Hongjinshen decoction in the treatment of pulmonary fibrosis based on network pharmacology and molecular docking

“…[ 24 ] Liu et al proposed that the anti-fibrotic molecule LINC00636 could inhibit MAPK1 by promoting the overexpression of miR-450a-2-3p, which ultimately exerts an ameliorative effect on cardiac fibrosis in patients with atrial fibrillation. [ 25 ] Therefore, MAPK1 may be a potential therapeutic target for antifibrotic therapy. Src is a non-receptor tyrosine kinase that integrates multiple extracellular signals and is associated with several human fibrotic diseases by promoting STAT3 phosphorylation to drive fibroblast proliferation.…”

Mechanism of action of non-coding RNAs and traditional Chinese medicine in myocardial fibrosis: Focus on the TGF-β/Smad signaling pathway

“…Similarly, lncRNA H19 expression is upregulated in cardiac fibrotic tissues and activated fibroblasts, while overexpression of DUSP5 abrogates the pro-proliferative effect of H19 in cardiac fibroblasts by a mechanism associated with inhibition of ERK1/2 phosphorylation ( Tao et al, 2016 ). In addition, MAPK1 has been reported to involve in various biological processes including myocardial fibrosis, and can be inhibited by exosomes containing LINC00636 by elevating the miR-450a-2-3p expression, thus alleviating the cardiac fibrosis in patients with AF ( Liu et al, 2021b ).…”

Extracellular Vesicles in Atrial Fibrillation—State of the Art

“…Interestingly, Liu et al demonstrated that AF patients presented decreased expression levels of EV-incorporated LINC00636 (Long Intergenic Non-Protein Coding RNA) and miR-450a-2-3p compared with non-AF patients. Moreover, the expression levels of these two RNAs positively correlated with each other [ 36 ]. Importantly, Chen et al proved that AF patients showed an increased expression of myocardial infarction associated transcript (MIAT) in serum-derived EVs when compared with healthy individuals.…”