Abstract
Cardiac fibrosis in the failing heart is modulated by activated myofibroblasts, and is a pathology marked by their deposition of extracellular matrix proteins. The TGFβ signaling pathway is important in stimulating fibrosis and therefore seems an attractive new target for anti-fibrotic therapy. The relationship between ncRNAs and TGFβ signaling pathway has been extensively studied. Here, we have provided several lines of evidence to prove that the fibrosis process could be regulated by miR-331 through targeting TGFβ signaling. First, bioinformatics analysis and dual luciferase assay validated a direct interaction between the miR-331 and TGFβ-R1 3′UTR sequence which results in the downregulation of TGFβ signaling pathway. Second, miR-331 expression was inversely related to the expression of a number of genes which are involved in extracellular matrix (ECM) production and deposition processes, both in the in vivo and in vitro fibrosis models. Third, in cultured mouse and human cardiac myofibroblasts (CMyoFbs) under ISO treatment, overexpression of miR-331 decreased the expression level of fibrosis-related genes. Consistently, western blot analysis confirmed that miR-331 overexpression ended in both Smad3 and Col1A1 protein level reduction in mouse cardiac myofibroblasts. Finally, flow cytometry analysis, cyclin D1 and D2 gene expression analysis, and wound-healing assay confirmed the inhibitory effect of miR-331 against cell proliferation and migration in ISO-treated cardiac myofibroblasts. Taken together, accumulative results showed that miR-331 reduced the level of fibrosis-related proteins in cardiac myofibroblasts culture via regulating TGFβ signaling pathway.
Highlights
Cardiac fibrosis in the failing heart is modulated by activated myofibroblasts, and is a pathology marked by their deposition of extracellular matrix proteins
Cardiac fibrosis commonly occurs in different types of cardiovascular diseases, such as diabetes, ischemic, aging heart disease, which results in heart failure and sudden cardiac death[35,36,37,38]
A critical event in cardiac fibrosis is the activation of cardiac fibroblasts (CFs) to myofibroblasts, which includes enhanced level of extracellular matrix (ECM) production and fibrotic processes following cardiac injury[33,39,40,41]
Summary
Cardiac fibrosis in the failing heart is modulated by activated myofibroblasts, and is a pathology marked by their deposition of extracellular matrix proteins. Accumulative results showed that miR-331 reduced the level of fibrosis-related proteins in cardiac myofibroblasts culture via regulating TGFβ signaling pathway. MCMyoFbs Mouse cardiac myofibroblasts HCMyoFbs Human cardiac myofibroblasts ECM Extracellular matrix CTGF Connective tissue growth factor ACTA2 Actin Alpha 2 LncRNA Long non-coding RNA circRNA Circular RNA CCND1/2 Cyclin D1/2 PPARγ Peroxisome Proliferator-Activated Receptor Gamma PFKP Phosphofructokinase, platelet Erk1/2 Extracellular signal-regulated kinase 1/2 PI3K Phosphoinositide-3-Kinase 3′UTR 3′Untranslated region MRS MicroRNA recognition site AngII Angiotensin II HPASMC Human Pulmonary Artery Smooth Muscle Cells n Number of sample CVF Collagen volume fraction RT-qPCR Real Time-quantitative Polymerase Chain Reaction. Inquiring the mechanisms of TGFβ signaling pathway in CFs may provide new approaches to treat cardiac fibrosis in cardiovascular diseases
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