Modulation of miR-10a-mediated TGF-β1/Smads signaling affects atrial fibrillation-induced cardiac fibrosis and cardiac fibroblast proliferation

Abstract

Atrial fibrillation (AF) rat models and rat cardiac fibroblasts (CFs) with overexpressed or inhibited miR-10a were used to investigate the possible role of miR-10a-mediated transforming growth factor-β (TGF-β1)/Smads signaling in cardiac fibrosis and fibroblast proliferation in rats with AF. Gene ontology and pathway enrichment analyses were used to identify the possible function of miR-10a in cardiac fibrosis. The results showed that overexpressed miR-10a significantly prolonged the duration of AF, further elevated the collagen volume fraction (CVF), and increased the viability of CFs in AF rats; these findings were in contrast with the findings for rats with inhibition of miR-10a (all P<0.05). Moreover, miR-10a overexpression could promote miR-10a, collagen-I, collagen III, α-SMA, and TGF-β1 protein expression and increase the levels of hydroxyproline but reduced Smad7 protein expression in atrial tissues and CFs in AF rats. Not surprisingly, inhibiting miR-10a led to completely contrasting results (all P<0.05). Moreover, TGF-β1 treatment could reverse the inhibitory effect of miR-10a down-regulation on cardiac fibrosis in CFs. Bioinformatics analysis and luciferase reporter assay results demonstrated that miR-10a bound directly to the 3′-UTR of BCL6, which is involved in cell growth and proliferation. Thus, our study indicate that down-regulation of miR-10a may inhibit collagen formation, reduce atrial structure remodeling, and decrease proliferation of CFs, eventually suppressing cardiac fibrosis in AF rats via inhibition of the TGF-β1/Smads signaling pathway.

Mycophenolate mofetil reduces epidural fibrosis by regulating TGF-β1/Smad2/3 axis to repress the proliferation, migration and differentiation of fibroblasts

“…Co-regulates the transcription of target genes with other transcription factors [36]. Many articles indicate that repress the TGF-β1 channel can inhibit broblasts functions [37][38][39].…”

<p>The Protective Role of Tanshinone IIA in Silicosis Rat Model via TGF-β1/Smad Signaling Suppression, NOX4 Inhibition and Nrf2/ARE Signaling Activation</p>

“…TGF-β1 is a powerful key fibrogenic cytokine. Many studies have confirmed that TGF-β1 plays an important regulatory role in cell proliferation, 11 differentiation, 12 migration, 13 immune regulation, 27 and extracellular matrix (ECM) transformation 28 in fibrotic diseases, and participates in tissue repair and fibrosis. The role of TGF-β1 in promoting fibrosis is mainly mediated by phosphorylating its downstream Smad proteins.…”

“…The role of TGF-β1 in promoting fibrosis is mainly mediated by phosphorylating its downstream Smad proteins. 11,14 TGF-β1/Smad signaling is identified as the main pathway of pulmonary fibrosis. The binding of TGF-β1 with its receptor II (TβRII) activates TGF-β1 receptor I (TβRI)'s kinase I. TβRI was phosphorylated and then phosphorylate Smad2 and Smad3, phosphorylated Smad2 and Smad3 afterwards bind to Smad 4 to constitute a Smad complex.…”

“…Among them, the transforming growth factor β1 (TGF-β1) plays a central role in fibrogenesis, which is widely convoluted in the development of fibrosis by interrupting the homeostasis microenvironment and promoting cell differentiation, migration, invasion or hyperplasia mainly through the TGF-β1/Smad signaling pathway. [11][12][13] It has been demonstrated that oxidative stress is a deleterious factor that is related to the profibrogenic activities of TGF-β1. There is a clear connection between TGF-β1 and oxidative stress during fibrogenesis.…”

Molecular Mechanisms, Diagnostic Aspects and Therapeutic Opportunities of Micro Ribonucleic Acids in Atrial Fibrillation

“…Li et al [87] used AF rat models and rat cardiac fibroblasts with overexpressed or inhibited miR-10a to investigate the possible role of miR-10a mediated TGF-β1 in rats with AF. They found that downregulation of miR-10a inhibits collagen formation, reduces atrial structure remodeling and decreases proliferation of cardiac fibroblasts, which leads to the suppression of cardiac fibrosis in AF rats via inhibition of the TGF-β1 signaling pathway.…”