Endoplasmic Reticulum Stress Aggravates Viral Myocarditis by Raising Inflammation Through the IRE1-Associated NF-κB Pathway
Endoplasmic Reticulum Stress Aggravates Viral Myocarditis by Raising Inflammation Through the IRE1-Associated NF-κB Pathway
复制标题
内质网应激通过 IRE1 相关的 NF-kappaB 通路引发炎症，从而加重病毒性心肌炎。
DOI：
10.1016/j.cjca.2015.03.003
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发表时间：
2015-08-01
影响因子：
6.2
通讯作者：
Xiong, Sidong
中科院分区：
文献类型：
--
作者：
Zha, Xi;Yue, Yan;Xiong, Sidong
背景：病毒性心肌炎以心肌炎症为特征，多由柯萨奇病毒感染引起。异常内质网应激参与许多心脏疾病，但其在病毒性心肌炎中的作用尚不清楚。方法：通过动态检测柯萨奇病毒B3 （CVB3）诱导的病毒性心肌炎中内质网应激的活性，分析其与心肌炎严重程度的关系，并通过化学激活剂tunicamycin （Tm）或抑制剂牛磺酸去氧胆酸（TUDCA）调节内质网应激的强度，探讨内质网应激对疾病发展的影响。揭示了cvb3诱导心肌炎内质网应激的潜在信号通路。结果：我们发现CVB3感染后心肌内质网应激标志物Grp78和Grp94的表达显著升高，且与心肌炎严重程度呈正相关。与此一致，tm增强内质网应激明显加重心肌炎，表现为心肌炎症加重，心功能降低，生存率降低，而TUDCA降低内质网应激，明显缓解心肌炎。内质网应激的这种病理效应可归因于促炎细胞因子（白细胞介素[IL]-6、IL-12、肿瘤坏死因子- α和单核细胞趋化蛋白-1）通过ire1相关的核因子- κ B （nf - κ B）途径产生的水平升高。结论：内质网应激通过ire1相关nf - κ B通路加重了cvb3诱导的心肌炎症。本研究有助于我们了解内质网应激在病毒性心肌炎中的作用，并促进基于内质网应激的相应治疗策略的发展。
Background: Viral myocarditis, which is mostly caused by coxsackievirus infection, is characterized by myocardial inflammation. Abnormal endoplasmic reticulum (ER) stress participates in many heart diseases, but its role in viral myocarditis remains unsolved.Methods: We investigated the influence of ER stress in coxsackievirus B3 (CVB3)-induced viral myocarditis by dynamically detecting its activation in CVB3-infected hearts, analyzing its association with myocarditis severity, and exploring its impact on disease development by modulating the strength of ER stress with the chemical activator tunicamycin (Tm) or the inhibitor tauroursodeoxycholic acid (TUDCA). The underlying signal pathway of ER stress in CVB3-induced myocarditis was also deciphered.Results: We found that myocardial expression of Grp78 and Grp94, 2 ER stress markers, was significantly increased after CVB3 infection and positively correlated with myocarditis severity. Consistently, Tm-augmented ER stress obviously aggravated myocarditis, as shown by more severe myocardial inflammation, reduced cardiac function, and a lower survival rate, whereas TUDCA decreased ER stress and obviously alleviated myocarditis. This pathologic effect of ER stress could be attributed to increased levels of proinflammatory cytokine (interleukin [IL]-6, IL-12, tumor necrosis factor-alpha, and monocyte chemoattractant protein-1) production through the IRE1-associated nuclear factor-kappa B (NF-kappa B) pathway.Conclusions: ER stress accentuated CVB3-induced myocardial inflammation through the IRE1-associated NF-kappa B pathway. This study may help us understand the role of ER stress in viral myocarditis and promote the development of corresponding therapeutic strategies based on manipulating ER stress.