Molecular Pathogenesis of Virus-Induced Myocardial Injury

病毒引起的心肌损伤的分子发病机制

• 批准号: 05044162
• 负责人: SASAYAMA Shigetake
• 金额: $ 6.4万
• 依托单位: Kyoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for international Scientific Research
• 财政年份: 1993
• 资助国家: 日本
• 起止时间: 1993 至 1994
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-05044162/
• 关键词: Virus; Reovirus; Myocarditis; Cardiomyopathy; PCR method; Molecular biology; 心筋細胞

Introduction To elucidate the mechanisms of viral myocarditis, much effort has been directed toward the immune response of the host, and relatively little has been done based on studies of the viruses themselves. Growth of a virus in a host cell is a major step in viral pathogenesis. Therefore, an understanding of viral determinants necessary for growth in heart tissue is important for elucidating the pathogenesis of viral myocarditis.Experiment 1 Two reovirus isolates (type 1 and type 3) differ in their capacity to grow in cultured mouse heart cells. The mammalian reoviruses contain a genome of 10 doublestranded RNA gene segments. By the use of 37 reassortant viruses (consisting of viruses with different combinations of genes derived from the two parents), difference in capacity of different strains to grow in heart cells was mapped to the M1 gene. The function of the M1 gene product, the mu2 protein, is largely unknown ; however, it is of particular interest that a mutation(s) in the … More M1 gene converts the virus to become myocarditic.Experiment 2 Two reovirus isolates also differ in their capacity to grow in cultured bovine aortic endothelial cells. By using 24 reassortant viruses, observed differences in the capacity of different strains to grow in cultured endothelial cells were also mapped to the M1 gene. No differences were detected in binding or proteolytic processing of viral outer capsid proteins of parental virions between the two reovirus isolates. Northern blot analysis showed a decreased production of viral mRNA in endothelial cells infected with type 3 reovirus, but not type 1. Thus, we have identified that the same M1 gene determines the growth capacity of reovirus in myocardial cells as well as endothelial cells. Humoral factors (such as TNF-alpha, interleukin 1, and IL 6) produced in virus-infected endothelial cells may participate in the pathogenesis of virus myocarditis in addition to the direct cytopathic effect of the virus in myocardial cells.Experiment 3 No reovirus genes were detected in myocardial samples (obtained by endomyocardial biopsy or autopsy) in 27 patients with myocarditis and dilated cardiomyopathy by the PCR method.Thus, reovirus in an attractive model in which to study how viruses cause myocarditis at a molecular genetic level. Less

简介 为了阐明病毒性心肌炎的机制，人们在宿主的免疫反应方面做了很多努力，而基于病毒本身的研究相对较少。病毒在宿主细胞中的生长是病毒发病机制的一个重要步骤。因此，了解心脏组织中生长所需的病毒决定因素对于阐明病毒性心肌炎的发病机制非常重要。实验1 两种呼肠孤病毒分离株（1型和3型）在培养的小鼠心脏细胞中生长的能力不同。哺乳动物呼肠孤病毒含有 10 个双链 RNA 基因片段的基因组。通过使用 37 种重配病毒（由具有来自两个亲本的不同基因组合的病毒组成），不同毒株在心脏细胞中生长的能力的差异被映射到 M1 基因。 M1 基因产物 mu2 蛋白的功能很大程度上未知；然而，特别令人感兴趣的是，M1 基因中的突变会将病毒转化为心肌病。实验 2 两种呼肠弧病毒分离株在培养的牛主动脉内皮细胞中生长的能力也有所不同。通过使用 24 种重配病毒，观察到的不同病毒株在培养的内皮细胞中生长能力的差异也被映射到 M1 基因。两种呼肠孤病毒分离株之间亲本病毒颗粒的病毒外衣壳蛋白的结合或蛋白水解加工没有检测到差异。 Northern印迹分析显示，感染3型呼肠孤病毒的内皮细胞中病毒mRNA的产生减少，但感染1型呼肠孤病毒则不然。因此，我们发现相同的M1基因决定了呼肠孤病毒在心肌细胞和内皮细胞中的生长能力。病毒感染的内皮细胞产生的体液因子（如TNF-α、白细胞介素1和IL 6）除了病毒对心肌细胞的直接细胞病变作用外，可能参与了病毒性心肌炎的发病机制。 实验3 27例病毒性心肌炎患者的心肌样本（通过心内膜心肌活检或尸检获得）中未检测到呼肠孤病毒基因。 因此，呼肠孤病毒是一个有吸引力的模型，可以在分子遗传水平上研究病毒如何引起心肌炎。较少的

项目成果

Matsui S et al: "Treatment of virus-induced myocardial injury with a novel immunomodulating agent, vesnarinone : suppression of natural killercell activity and tumor necrosis factor-alpha production." J Clin Invest. 94. 1212-1217 (1994)

Matsui S 等人：“用新型免疫调节剂 vesnarinone 治疗病毒引起的心肌损伤：抑制自然杀伤细胞活性和肿瘤坏死因子-α 的产生。”

Matsui S et al: "Vesnarinone prolongs survival and reduces lethality in a murine model oflethal endotoxemia." Life Sci. 55. 1735-1741 (1994)

Matsui S 等人：“Vesnarinone 可延长致命性内毒素血症小鼠模型的存活率并降低致死率。”

Matsumori A et al: "Increased circulating cytokinesin patients with cardiomyopathy and myocarditis." Br Heart J. 72. 561-566 (1994)

Matsumori A 等人：“患有心肌病和心肌炎的患者循环细胞因子增多。”

Matsumori A: "Idiopathic Dilated Cardiomyopathy:Animal models for therapeutic trials of viral myocarditis.Vesnarinone prolongs survival and reduces lethality in a murine model of lethal endotoxemia." Springer-Verlag, 12 (1993)

Matsumori A：“特发性扩张型心肌病：用于病毒性心肌炎治疗试验的动物模型。维纳里酮可延长致命性内毒素血症小鼠模型的存活率并降低致死率。”

Suzuki H et al: "Enhanced expression of superoxide dismutase messenger RNA in viral myocarditis. An-SH dependent reduction of its expression and myocardial injury." J Clin Invest. 91. 2727-2733 (1993)

Suzuki H 等人：“病毒性心肌炎中超氧化物歧化酶信使 RNA 的表达增强。An-SH 依赖性减少其表达和心肌损伤。”