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.
Highlights
Atrial fibrillation (AF) is one of the most common sustained supraventricular arrhythmias that increase the risk of stroke [1]
GO functional annotation was performed on the potential target genes at the three levels: biological process (BP), cellular component (CC), and molecular function (MF)
The scratch assay showed that the inhibitory effect of miR-450a2-3p mimic on human umbilical vein endothelial cells (HUVECs) migration was markedly abolished by mitogen-activated protein kinase 1 (MAPK1) (Figure 8(b)). These findings suggest that miR450a-2-3p is dependent on MAPK1 to regulate cardiac fibroblasts (CFs) proliferation and endothelial-mesenchymal transition (EMT) in HUVECs
Summary
Atrial fibrillation (AF) is one of the most common sustained supraventricular arrhythmias that increase the risk of stroke [1]. The underlying mechanism is thought to be associated with electrical and structural atrial remodeling, which lead to cardiac fibrosis [2, 3]. CFs can differentiate into myofibroblasts, the cells that present a 2-fold higher ability to synthesize collagen, including alpha smooth muscle actin (αSMA) [5]. In physiological conditions cardiac fibrosis is low, differentiation of monocytes, endothelial cells, bone marrow circulating progenitor cells, and peripheral cells in pathological conditions increase cardiac fibrosis [6,7,8]. Endothelial-mesenchymal transition (EMT) in endothelial cells is closely related to cardiac fibrosis. The molecular mechanisms of cardiac fibrosis and EMT in AF are largely unclear
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