Seoul Center, Korea Basic Science Institute, Sungbuk-gu, Seoul 136-713, Republic of Korea.
BMC Genomics. 2011 Oct 20;12:520. doi: 10.1186/1471-2164-12-520.
To investigate the molecular and cellular pathogenesis underlying myocarditis, we used an experimental autoimmune myocarditis (EAM)-induced heart failure rat model that represents T cell mediated postinflammatory heart disorders.
By performing unbiased 2-dimensional electrophoresis of protein extracts from control rat heart tissues and EAM rat heart tissues, followed by nano-HPLC-ESI-QIT-MS, 67 proteins were identified from 71 spots that exhibited significantly altered expression levels. The majority of up-regulated proteins were confidently associated with unfolded protein responses (UPR), while the majority of down-regulated proteins were involved with the generation of precursor metabolites and energy metabolism in mitochondria. Although there was no difference in AKT signaling between EAM rat heart tissues and control rat heart tissues, the amounts and activities of extracellular signal-regulated kinase (ERK)-1/2 and ribosomal protein S6 (rpS6) were significantly increased. By comparing our data with the previously reported myocardial proteome of the Coxsackie viruses of group B (CVB)-mediated myocarditis model, we found that UPR-related proteins were commonly up-regulated in two murine myocarditis models. Even though only two out of 29 down-regulated proteins in EAM rat heart tissues were also dysregulated in CVB-infected rat heart tissues, other proteins known to be involved with the generation of precursor metabolites and energy metabolism in mitochondria were also dysregulated in CVB-mediated myocarditis rat heart tissues, suggesting that impairment of mitochondrial functions may be a common underlying mechanism of the two murine myocarditis models.
UPR, ERK-1/2 and S6RP signaling were activated in both EAM- and CVB-induced myocarditis murine models. Thus, the conserved components of signaling pathways in two murine models of acute myocarditis could be targets for developing new therapeutic drugs or methods aimed at treating enigmatic myocarditis.
为了研究心肌炎的分子和细胞发病机制，我们使用了实验性自身免疫性心肌炎（EAM）诱导的心力衰竭大鼠模型，该模型代表了 T 细胞介导的炎症后心脏疾病。
通过对对照大鼠心脏组织和 EAM 大鼠心脏组织的蛋白质提取物进行无偏 2 维电泳，然后进行纳升 HPLC-ESI-QIT-MS，从 71 个斑点中鉴定出 67 个蛋白质，这些蛋白质的表达水平发生了显著变化。上调的大多数蛋白质与未折叠蛋白反应（UPR）密切相关，而下调的大多数蛋白质则与线粒体前体代谢物和能量代谢的产生有关。尽管 EAM 大鼠心脏组织和对照大鼠心脏组织之间的 AKT 信号没有差异，但细胞外信号调节激酶（ERK）-1/2 和核糖体蛋白 S6（rpS6）的量和活性显著增加。通过将我们的数据与先前报道的 B 组柯萨奇病毒（CVB）介导的心肌炎模型的心肌蛋白质组进行比较，我们发现 UPR 相关蛋白在两种鼠心肌炎模型中均上调。尽管 EAM 大鼠心脏组织中下调的 29 个蛋白中只有两个在 CVB 感染的大鼠心脏组织中也失调，但其他已知与线粒体前体代谢物和能量代谢有关的蛋白也在 CVB 介导的心肌炎大鼠心脏组织中失调，表明线粒体功能障碍可能是两种鼠心肌炎模型的共同潜在机制。
UPR、ERK-1/2 和 S6RP 信号在 EAM 和 CVB 诱导的心肌炎鼠模型中均被激活。因此，两种急性心肌炎鼠模型中信号通路的保守成分可能是开发旨在治疗神秘心肌炎的新治疗药物或方法的靶点。
