Involvement of Endoplasmic Reticulum Stress-Mediated C/EBP Homologous Protein Activation in Coxsackievirus B3-Induced Acute Viral Myocarditis
Involvement of Endoplasmic Reticulum Stress-Mediated C/EBP Homologous Protein Activation in Coxsackievirus B3-Induced Acute Viral Myocarditis
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内质网应激介导的 C/EBP 同源蛋白激活参与柯萨奇病毒 B3 诱导的急性病毒性心肌炎
DOI：
10.1161/circheartfailure.114.001244
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发表时间：
2015-07-01
影响因子：
9.7
通讯作者：
Wang, Jian'an
中科院分区：
文献类型：
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作者：
Cai, Zhejun;Shen, Li;Wang, Jian'an
背景-本研究验证了内质网(ER)应激/C/EBP同源蛋白(CHOP)信号与柯萨奇病毒B3(CVB3)诱导的急性病毒性心肌炎(AVMC)之间是否存在联系的假说。方法和结果：通过腹腔注射1000组织培养感染量(TCID50)的CVB3病毒诱导小鼠AVMC。在AVMC小鼠心脏(n=11)，与对照组(n=10)相比，内质网应激和CHOP被显著激活，并与诱导细胞凋亡信号通路有关，包括Bcl2的减少、Bax和caspase3的激活，而内质网应激抑制剂牛磺熊去氧胆酸可显著阻断这些作用(n=11)。此外，化学抑制内质网应激显著减少心肌细胞的凋亡，阻止心肌肌钙蛋白I的升高，改善血流动力学和超声心动图评价的心功能障碍，减少病毒复制，提高CVB3接种后的存活率。我们进一步发现，与野生型CVB3接种组(n=10)相比，CHOP基因消融(n=10)抑制了心肌细胞内Bcl2/Bax比值的降低和caspase3的激活，并阻止了心肌细胞的凋亡。CHOP缺失对CVB3诱导的AVMC的心脏损伤、心功能障碍、病毒复制和存活有显著的保护作用。结论：我们的研究结果提示，ER应激/CHOP信号通路参与了CVB3诱导的AVMC，为AVMC的治疗提供了一种新的策略。
Background-This study tested the hypothesis whether endoplasmic reticulum (ER) stress/C/EBP homologous protein (CHOP) signaling is linked with coxsackievirus B3 (CVB3)-induced acute viral myocarditis (AVMC) in vivo.Methods and Results-AVMC was induced by intraperitoneal injection of 1000 tissue culture infectious dose (TCID50) of CVB3 virus in mice. In AVMC mouse hearts (n=11), ER stress and CHOP were significantly activated, and were linked to the induction of proapoptotic signaling including reduction of Bcl-2, activation of Bax and caspase 3, compared with the controls (n=10), whereas these could be markedly blocked by ER stress inhibitor tauroursodeoxycholic acid administration (n=11). Moreover, chemical inhibition of ER stress significantly attenuated cardiomyocytes apoptosis, and prevented cardiac troponin I elevation, ameliorated cardiac dysfunction assessed by both hemodynamic and echocardiographic analysis, reduced viral replication, and increased survival rate after CVB3 inoculation. We further discovered that genetic ablation of CHOP (n=10) suppressed cardiac Bcl-2/Bax ratio reduction and caspase 3 activation, and prevented cardiomyotes apoptosis in vivo, compared with wild-type receiving CVB3 inoculation (n=10). Strikingly, CHOP deficiency exhibited dramatic protective effects on cardiac damage, cardiac dysfunction, viral replication, and promoted survival in CVB3-caused AVMC.Conclusions-Our data imply the involvement of ER stress/CHOP signaling in CVB3-induced AVMC via proapoptotic pathways, and provide a novel strategy for AVMC treatment.