ADAR1p150 Forms a Complex with Dicer to Promote miRNA-222 Activity and Regulate PTEN Expression in CVB3-Induced Viral Myocarditis.

Xincai Zhang,Yuanyi Zuo,Jun Hu,Yuxin Xie,Xiangting Gao,Hongfei Xu,Shaohua Zhu

doi:10.3390/ijms20020407

Xincai Zhang, Yuanyi Zuo + Show 5 more

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https://doi.org/10.3390/ijms20020407

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Abstract

Adenosine deaminases acting on RNA (ADAR) are enzymes that regulate RNA metabolism through post-transcriptional mechanisms. ADAR1 is involved in a variety of pathological conditions including inflammation, cancer, and the host defense against viral infections. However, the role of ADAR1p150 in vascular disease remains unclear. In this study, we examined the expression of ADAR1p150 and its role in viral myocarditis (VMC) in a mouse model. VMC mouse cardiomyocytes showed significantly higher expression of ADAR1p150 compared to the control samples. Coimmunoprecipitation verified that ADAR1p150 forms a complex with Dicer in VMC. miRNA-222, which is involved in many cardiac diseases, is highly expressed in cardiomyocytes in VMC. In addition, the expression of miRNA-222 was promoted by ADAR1p150/Dicer. Among the target genes of miRNA-222, the expression of phosphatase-and-tensin (PTEN) protein was significantly reduced in VMC. By using a bioinformatics tool, we found a potential binding site of miRNA-222 on the PTEN gene’s 3′-UTR, suggesting that miRNA-222 might play a regulatory role. In cultured cells, miR-222 suppressed PTEN expression. Our findings suggest that ADAR1p150 plays a key role in complexing with Dicer and promoting the expression of miRNA-222, the latter of which suppresses the expression of the target gene PTEN during VMC. Our work reveals a previously unknown role of ADAR1p150 in gene expression in VMC.

Highlights

It has been well documented that viral myocarditis (VMC) is a primary cause of sudden death and heart failure in young adults [1,2,3]
We found that the expression of ADAR1p150 was elevated in cardiomyocytes from the VMC mnwwrmnwaeeiihitiotcotchinehcnela,eaW,CWaCrtwAtwdBaeBaelhiVDlhVfofiroir3Amlo3aleuaeutfRtfynoAoncA1odcrradDapcD4rt4ry1hdA8tdA8t1haieihR0oahRtosmt1tm(w1((hFptFpNyehayi1i1gosgReo1e1ucu0cxnC0eyryproxe)wtewtr,etpee2Hs2assarsCCisess(9g()sNi)Nncn.ons.2oiRnioRofitcCtonCcesfsa)l)i,oiln,AggsfHtnH,nDlAaiy9i9fAfnciDcicc2dcR2haAa1anccncRpenatetll1r1gllylydl5spes,0ic,d1caah5wahc(na0nFafiadndniwsbgggceruceaeaoladrsedrbrevdedl((a2ailFiFaetBsaieicvtgc)gds.aufuf(StiiriCebrnibeemdrFrco2o2)aiibBlbnBrtaldh)la)r.ac.aissoarSttStermsisihmsdm(uay(iCioCdloiltlaFmcaFsbry)r)wyettreteroheehesncsarsayifeutuntrtlofhelfthotemssasaucdwfdtwntrehodbedbeemrereieweVenenntfMifnhtoioinhneueCufofnCenVenmcdBcdMattieVteciiadnCedn3l, for 48 h (Figure 2C). 2.3
We argue that the elevated miRNA-222 levels observed in the hearts of VMC mice are likely to contribute to the VMC pathogenesis

Summary

Introduction

It has been well documented that viral myocarditis (VMC) is a primary cause of sudden death and heart failure in young adults [1,2,3]. Coxsackievirus B3 (CVB3), belonging to the Picornaviridae family of genus Enterovirus [4], is regarded as the most common infectious pathogen responsible for VMC and the subsequent pathogenesis of dilated cardiomyopathy (DCM) [5]. Consistent with this, another study identified acute myocarditis as the cause of death at a rate of ~1.5% in a total of 2560 autopsies but was suspected in only one of the cases in the clinic [12].

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