Circular RNA mmu_circ_0005019 inhibits fibrosis of cardiac fibroblasts and reverses electrical remodeling of cardiomyocytes

Na Wu,Bin Xu,Xiaoyue Jia,Li Zhong,Ying Xiang,Long Wu,Zhiquan Yuan,Yafei Li,Chengying Li

doi:10.1186/s12872-021-02128-w

Abstract

BackgroundCircular RNA (circRNA) have been reported to play important roles in cardiovascular diseases including myocardial infarction and heart failure. However, the role of circRNA in atrial fibrillation (AF) has rarely been investigated. We recently found a circRNA hsa_circ_0099734 was significantly differentially expressed in the AF patients atrial tissues compared to paired control. We aim to investigate the functional role and molecular mechanisms of mmu_circ_0005019 which is the homologous circRNA in mice of hsa_circ_0099734 in AF.MethodsIn order to investigate the effect of mmu_circ_0005019 on the proliferation, migration, differentiation into myofibroblasts and expression of collagen of cardiac fibroblasts, and the effect of mmu_circ_0005019 on the apoptosis and expression of Ito, INA and SK3 of cardiomyocytes, gain- and loss-of-function of cell models were established in mice cardiac fibroblasts and HL-1 atrial myocytes. Dual-luciferase reporter assays and RIP were performed to verify the binding effects between mmu_circ_0005019 and its target microRNA (miRNA).ResultsIn cardiac fibroblasts, mmu_circ_0005019 showed inhibitory effects on cell proliferation and migration. In cardiomyocytes, overexpression of mmu_circ_0005019 promoted Kcnd1, Scn5a and Kcnn3 expression. Knockdown of mmu_circ_0005019 inhibited the expression of Kcnd1, Kcnd3, Scn5a and Kcnn3. Mechanistically, mmu_circ_0005019 exerted biological functions by acting as a miR-499-5p sponge to regulate the expression of its target gene Kcnn3.ConclusionsOur findings highlight mmu_circ_0005019 played a protective role in AF development and might serve as an attractive candidate target for AF treatment.

Highlights

Circular RNA have been reported to play important roles in cardiovascular diseases including myocardial infarction and heart failure
Mmu_circ_0005019 knockdown promotes cardiac fibroblasts migration We examined the effects of mmu_circ_0005019 knockdown on cell proliferation, migration, differentiation into myofibroblasts and expression of collagen
In contrast to the gain-offunction cell models, the transwell assays showed that knockdown of mmu_circ_0005019 significantly promoted the migration of cardiac fibroblasts (Fig. 2C)

Summary

Introduction

Circular RNA (circRNA) have been reported to play important roles in cardiovascular diseases including myocardial infarction and heart failure. The role of circRNA in atrial fibrillation (AF) has rarely been investigated. We recently found a circRNA hsa_circ_0099734 was significantly differentially expressed in the AF patients atrial tissues compared to paired control. We aim to investigate the functional role and molecular mechanisms of mmu_ circ_0005019 which is the homologous circRNA in mice of hsa_circ_0099734 in AF. The estimated prevalence is 1–2% in the general population, increasing with the age [1]. Ectopic activity can provide the trigger, while structural and electrical remodeling provide the substrate for AF perpetuation [7]. Atrial fibrosis is the hallmark of structural remodeling. Cardiomyocyte apoptosis, increased connective tissue and inflammatory cells infiltration are present during structural remodeling [8].

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