Janus effects of ADAR1 on CVB3-induced viral myocarditis at different infection stages
Janus effects of ADAR1 on CVB3-induced viral myocarditis at different infection stages
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ADAR1对不同感染阶段CVB3诱导的病毒性心肌炎的Janus作用
DOI：
10.1016/j.ijcard.2016.08.315
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发表时间：
2016-11-15
影响因子：
3.5
通讯作者：
Xiong, Sidong
中科院分区：
文献类型：
--
作者：
Dong, Ning;Dong, Chunsheng;Xiong, Sidong
背景：柯萨奇病毒（CVB3）感染是病毒性心肌炎（VMC）最常见的病因，其特征为病毒感染和心肌炎症。作用于RNA的干扰素（IFN）诱导的腺苷脱氨酶ADAR1据报道在多种病毒中发挥作用。近期研究表明，ADAR1根据病毒类型具有抗病毒作用或促进病毒复制。
目的：本研究旨在探讨ADAR1是否影响CVB3诱导的病毒性心肌炎。
方法：我们通过CVB3感染构建了急性病毒性心肌炎小鼠模型。通过体内聚乙烯亚胺介导的ADAR1上调/下调质粒递送调控ADAR1的表达。
结果：我们的研究表明，CVB3感染后ADAR1表达上调。在病毒感染早期下调ADAR1可改善CVB3诱导的病毒性心肌炎。在此阶段，病毒复制是引发炎症反应的关键。如ADAR1下调时干扰素-β升高和病毒载量降低所示，ADAR1可能主要通过病毒复制影响炎症。然而，当在病毒感染的中晚期炎症反应已经建立时，ADAR1下调会加重疾病进展。在此阶段，蛋白质印迹分析表明ADAR1可能通过PKR和NF -κB信号通路直接影响炎症反应。
结论：我们证明了在CVB3诱导的病毒性心肌炎的早期或中晚期，ADAR1表现出双刃剑效应。我们的研究结果可能为病毒性心肌炎的治疗提供新的见解。（C）2016爱思唯尔爱尔兰有限公司。保留所有权利。
Background: Coxsackievirus (CVB3) infection is the most common cause of viral myocarditis (VMC) characterized by viral infection and myocardial inflammation. ADAR1, the interferon (IFN)-inducible adenosine deaminase acting on RNA, has been reported to be functional in various viruses. Recent studies have demonstrated that ADAR1 holds an antiviral role or promotes viral replication depending on virus type.Objectives: This study aims to investigate whether or not ADAR1 affects CVB3-induced VMC.Methods: We generated an acute VMC mouse model by CVB3 infection. ADAR1 expression was manipulated by in vivo polyethyleneimine-mediated ADAR1 up/down-regulation plasmid delivery.Results: Our study indicated that ADAR1 was up-regulated after CVB3 infection. ADAR1 down-regulation in the early stage of viral infection ameliorated CVB3-induced VMC. In this stage, viral replication was a key point to initiate inflammatory response. ADAR1 may affect inflammation mainly through viral replication as shown by the elevated IFN-beta and decreased viral load with ADAR1 down-regulation. However, when the inflammatory response was established in the middle-late stage of viral infection, ADAR1 down-regulation aggravated disease progression. In this stage, Western blot analysis indicated that ADAR1 may directly influence inflammatory response through PKR and NF-kappa B signaling.Conclusion: We demonstrated that ADAR1 exhibited double-edged effects during the early or middle-late stage of CVB3-induced VMC. Our findings may provide new insights into the therapeutic treatments of VMC. (C) 2016 Elsevier Ireland Ltd. All rights reserved.