Identification of Cardiac CircRNAs in Mice With CVB3-Induced Myocarditis

Xiang Nie,Dao Wen Wang,Chen Chen,Jiahui Fan,Jin Wang,Huihui Li,Rong Xie

doi:10.3389/fcell.2022.760509

Abstract

Background: Viral myocarditis could initiate various immune response to the myocardium, resulting in myocyte damage and subsequent cardiac dysfunction. The expression profile and functions of circRNAs in this process are unknown. Methods: Fulminant myocarditis (FM) and non-FM models were induced by coxsackie B3 virus (CVB3) infection in A/J mice and C57BL/6 mice, respectively. CircRNAs expression profile was identified by RNA-seq. Quantitative RT-PCR, Spearman rank correlation, KEGG pathway, GO analysis, Western blot and flow cytometry were performed for functional analysis. Results: Severer inflammatory cell infiltration and cardiomyocyte necrosis were presented in CVB3-treated A/J mice than those in C57BL/6 mice. The dysregulated circRNAs in both of the mouse strains displayed strong correlation with the immune response, but dysregulated circRNAs in A/J mice were more prone to cardiac dysfunction. KEGG analysis indicated that the target genes of dysregulated circRNAs in A/J mice were mainly involved in viral infection, T cell and B cell receptor signaling pathways, while the target genes of dysregulated circRNAs in C57BL/6 mice were unrelated to immune pathways. Furthermore, knockdown of circArhgap32 that was downregulated in CVB3-treated A/J mice promoted cardiomyocyte apoptosis in vitro. Conclusion: Our data showed that cardiac circRNAs dysregulation is an important characteristic of viral myocarditis.

Highlights

Acute myocarditis (AM) has been defined as a clinical manifestation of cardiac inflammation leading to myocardial damage, fibrosis and heart failure (Gupta et al, 2008)
A/J mice are more susceptible to CVB3induced myocarditis than C57BL/6 mice (Gauntt and Huber, 2003)
67 circRNAs were upregulated and 32 circRNAs were downregulated in the hearts of CVB3-treated A/J mice, while 95 circRNAs were upregulated and 33 circRNAs were downregulated in the hearts of CVB3-treated C57BL/6 mice (Figure 1E)

Summary

Introduction

Acute myocarditis (AM) has been defined as a clinical manifestation of cardiac inflammation leading to myocardial damage, fibrosis and heart failure (Gupta et al, 2008). Infection by cardiotropic viruses triggers different symptoms, varying from severe myocarditis to mild or asymptomatic presentation. The molecular mechanisms underlying the various clinical presentation and CircRNAs in Myocarditis severity of AM are largely elusive. It was well-recognized that A/J mice showed a higher susceptibility towards viral infection than C57BL/6 mice. Histological examination showed regional myocardial inflammatory infiltrations in the initial stage, almost all signs of inflammation in the hearts of CVB3treated C57BL/6 mice disappeared 21 days after infection (Turk, 1978; Gauntt and Huber, 2003; Corsten et al, 2012; Garmaroudi et al, 2015). The expression profile and functions of circRNAs in this process are unknown

Methods

Results

Conclusion