Dystrophin disruption in enterovirus-induced myocarditis and dilated cardiomyopathy: from bench to bedside
Dystrophin disruption in enterovirus-induced myocarditis and dilated cardiomyopathy: from bench to bedside
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DOI：
10.1007/s00430-003-0189-7
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发表时间：
2004-05-01
影响因子：
5.4
通讯作者：
Knowlton, KU
中科院分区：
文献类型：
--
作者：
Badorff, C;Knowlton, KU
肌营养不良蛋白-糖蛋白复合物（DGC）的遗传缺陷导致遗传性扩张型心肌病。肠病毒也可以引起心肌病，我们之前已经描述了肠病毒诱导的扩张型心肌病的一种机制：肠病毒蛋白酶2A直接在铰链3区域切割肌营养不良蛋白，导致功能性肌营养不良蛋白损伤。在感染柯萨奇病毒B3的小鼠中，病毒感染的心肌细胞中心脏DGC被破坏，肌层完整性丧失。此外，体内肌营养不良蛋白缺乏显著增加肠病毒诱导的心肌病，提示肌营养不良蛋白裂解在肠病毒诱导的心肌病中起致病作用。在这里，我们将这些实验结果扩展到一例柯萨奇病毒B2型心肌炎引起的扩张型心肌病患者。心内膜活检标本显示炎症浸润和肌细胞溶解。肠病毒衣壳抗原VP1的免疫染色显示病毒感染的心肌细胞。心肌细胞的病灶区域显示肌营养不良蛋白和β -肌糖聚糖的肌上皮染色模式的缺失，与先前在病毒感染的小鼠心脏中发现的结果相同。在体外，柯萨奇病毒B2蛋白酶2A可切割人肌营养不良蛋白。这些发现表明，在人类柯萨奇病毒B型心肌炎中，DGC的局灶性破坏可能主要发生，并可能有助于人类肠病毒诱导的扩张型心肌病的发病机制。
Genetic defects of the dystrophin-glycoprotein complex (DGC) cause hereditary dilated cardiomyopathy. Enteroviruses can also cause cardiomyopathy and we have previously described a mechanism involved in enterovirus-induced dilated, cardiomyopathy: The enteroviral protease 2A directly cleaves dystrophin in the hinge 3 region, leading to functional dystrophin impairment. During infection of mice with coxsackievirus B3, the DGC in the heart is disrupted and the sarcolemmal integrity is lost in virus-infected cardiomyocytes. Additionally, dystrophin deficiency markedly increases enterovirus-induced cardiomyopathy in vivo, suggesting a pathogenetic role of the dystrophin cleavage in enterovirus-induced cardiomyopathy. Here, we extend these experimental findings to a patient with dilated cardiomyopathy due to a coxsackievirus B2 myocarditis. Endomyocardial biopsy specimens showed an inflammatory infiltrate and myocytolysis. Immuno-staining for the enteroviral capsid antigen VP1 revealed virus-infected cardiomyocytes. Focal areas of cardiomyocytes displayed a loss of the sarcolemmal staining pattern for dystrophin and beta-sarcoglycan identical to previous findings in virus-infected mouse hearts. In vitro, coxsackievirus B2 protease 2A cleaved human dystrophin. These findings demonstrate that in human coxsackievirus B myocarditis a focal disruption of the DGC can principally occur and may contribute to the pathogenesis of human enterovirus-induced dilated cardiomyopathy.