Novel role of the clustered miR-23b-3p and miR-27b-3p in enhanced expression of fibrosis-associated genes by targeting TGFBR3 in atrial fibroblasts.

Zhenzhen Yang,Zhixin Shan,Xi‐Long Zheng,Hui Li,Shujing Yuan,Wenyan Dong,Xianhong Fang,Jing Yang,Rong Pan,Jiening Zhu,Shulin Wu,Jingnan Liang,Huiming Guo,Zhen Xiao

doi:10.1111/jcmm.14211

Abstract

Atrial fibrillation (AF) is the most common type of arrhythmia in cardiovascular diseases. Atrial fibrosis is an important pathophysiological contributor to AF. This study aimed to investigate the role of the clustered miR‐23b‐3p and miR‐27b‐3p in atrial fibrosis. Human atrial fibroblasts (HAFs) were isolated from atrial appendage tissue of patients with sinus rhythm. A cell model of atrial fibrosis was achieved in Ang‐II‐induced HAFs. Cell proliferation and migration were detected. We found that miR‐23b‐3p and miR‐27b‐3p were markedly increased in atrial appendage tissues of AF patients and in Ang‐II‐treated HAFs. Overexpression of miR‐23b‐3p and miR‐27b‐3p enhanced the expression of collagen, type I, alpha 1 (COL1A1), COL3A1 and ACTA2 in HAFs without significant effects on their proliferation and migration. Luciferase assay showed that miR‐23b‐3p and miR‐27b‐3p targeted two different sites in 3ʹ‐UTR of transforming growth factor (TGF)‐β1 receptor 3 (TGFBR3) respectively. Consistently, TGFBR3 siRNA could increase fibrosis‐related genes expression, along with the Smad1 inactivation and Smad3 activation in HAFs. Additionally, overexpression of TGFBR3 could alleviate the increase of COL1A1, COL3A1 and ACTA2 in HAFs after transfection with miR‐23b‐3p and miR‐27b‐3p respectively. Moreover, Smad3 was activated in HAFs in response to Ang‐II treatment and inactivation of Smad3 attenuated up‐regulation of miR‐23b‐3p and miR‐27b‐3p in Ang‐II‐treated HAFs. Taken together, these results suggest that the clustered miR‐23b‐3p and miR‐27b‐3p consistently promote atrial fibrosis by targeting TGFBR3 to activate Smad3 signalling in HAFs, suggesting that miR‐23b‐3p and miR‐27b‐3p are potential therapeutic targets for atrial fibrosis.

Highlights

Atrial fibrillation (AF) is the most common type of arrhythmia in cardiovascular diseases
The RT‐qPCR results showed that mRNA expression of the above fibrosis‐related genes was significantly up‐regulated in atrial appendages of AF patients (P < 0.05 respectively) (Figure 1B)
We observed the obvious increase of fibrosis in atrial append‐ age tissue of patients with sinus rhythm, along with the significant elevation of COL1A1, COL3A1 and ACTA2

Summary

Introduction

Atrial fibrillation (AF) is the most common type of arrhythmia in cardiovascular diseases. The incidence and prevalence of AF in‐ crease as the population ages.[1]. Atrial electrical remodeling and structural remodeling are important aspects of the pathogenesis of AF.[2]. Much progress has been made during the past several decades, the mechanisms and pathophysiology of AF are still not well elucidated. Atrial fibrosis has been known as an im‐ portant pathophysiological contributor and has been linked to AF recurrences and resistance to clinical therapy. Increasing ev‐ idence indicates that fibrosis plays a central role in stabilizing the re‐entrant drivers that maintain the arrhythmia.[3-5]. To prevent AF through suppressing fibrosis has been supported experimentally and accepted as a promising potential therapeutic strategy for AF patients.[6]

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Conclusion