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

Peng-Fei Li,Rui Li,Shao-Bo Shi,Bo Yang,Qiong-Tao Wang,Rong-Hua He,Guo-Tao Rao

doi:10.1042/bsr20181931

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.

Highlights

Atrial fibrillation (AF), widely considered the most common cardiac rhythm disorder, significantly increases the risk of morbidity and mortality from shock and heart failure and has rapidly become a major medical problem worldwide [1,2,3]
Rats were randomly divided into four groups of ten animals each: Control, Model (AF rat models injected with the same volume of a vehicle control), agomiR-10a (AF rat models injected with agomiR-10a), and antagomiR-10a (AF rat models injected with antagomiR-10a)
The agomiR-10a group had a prolonged duration of AF, whereas the antagomiR-10a group showed deceased AF durations compared with Model AF rats (Figure 2, all P

Summary

Introduction

Atrial fibrillation (AF), widely considered the most common cardiac rhythm disorder, significantly increases the risk of morbidity and mortality from shock and heart failure and has rapidly become a major medical problem worldwide [1,2,3]. The pathogenesis of AF is extremely complex and is reportedly associated with various factors, such as atrial structural remodeling, electrical remodeling, inflammation, autonomic nervous system dysfunction, and oxidative stress, amongst other factors [4,5,6,7]. The formation of cardiac fibrosis plays a key role in the incidence and development of cardiac structural remodeling, which may constitute an important component of AF pathogenesis [10]. MiRNAs are small noncoding RNA molecules consisting of 22–25 nts. They can regulate target genes at the post-transcriptional level by degrading their target mRNAs or inhibiting their translation [11,12]. MiRNA (miR)-10a is a member of the miR-10 family, which has been shown to play a direct role in the proliferation and differentiation of several cell types [13]. MiR-10a has been shown to be closely related to the occurrence and progression of cardiovascular-related diseases, License 4.0 (CC BY)

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