Cardiac Deletion of the Coxsackievirus-Adenovirus Receptor Abolishes Coxsackievirus B3 Infection and Prevents Myocarditis In Vivo
Cardiac Deletion of the Coxsackievirus-Adenovirus Receptor Abolishes Coxsackievirus B3 Infection and Prevents Myocarditis In Vivo
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DOI：
10.1016/j.jacc.2008.10.064
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发表时间：
2009-04-07
影响因子：
24
通讯作者：
Gotthardt, Michael
中科院分区：
文献类型：
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作者：
Shi, Yu;Chen, Chen;Gotthardt, Michael
目的 我们研究了柯萨奇病毒腺病毒受体 (CAR) 在病毒性心肌炎中的作用。背景 CAR 参与多种细胞类型的病毒摄取。因此，它被建议作为预防或治疗柯萨奇病毒 B3 (CVB3) 诱发的疾病如心肌炎和心肌病的治疗靶点。最近对 CAR 缺陷动物的研究表明，CAR 在胚胎发育和重塑以及心脏畸形和致死中发挥作用。方法我们生成了一只他莫昔芬诱导敲除 (KO) 小鼠来研究 CVB3 感染后成年心脏中的 CAR。将 CAR-KO 与表达野生型 CAR (WT) 的非诱导同窝对照动物的组织形态学、病毒分布和心脏功能进行比较。结果我们已经证明，消除 CAR 可以预防炎症性心肌病的迹象，并且 KO 心脏中基本上没有病理学。与 CVB3 感染的 WT 对照动物不同，心脏诱导型 KO 小鼠在 CVB3 感染后没有表现出结构变化，例如单核细胞浸润或纤维化，也没有表现出炎症标记物（例如白细胞介素 6 和 -10）产生的增加。 CVB3 感染导致表达 WT 的动物心脏出现严重的收缩功能障碍，而 CAR 缺陷的心脏则表现正常。 结论 消除成人心脏中的 CAR 可以有效阻止病毒进入和包括收缩功能障碍在内的相关病理。 CVB3 感染的 KO 心脏中缺乏浸润或其他形态学变化，强调了直接病毒介导的病理学在肠道病毒性心肌炎中的作用。 （J Am Coll Cardiol 2009；53：1219-26）(C) 2009 年，美国心脏病学会基金会
Objectives We investigated the role of the Coxsackievirus-adenovirus receptor (CAR) in viral myocarditis.Background CAR is involved in virus uptake into various cell types. It has therefore been suggested as a therapeutic target to prevent or treat Coxsackievirus B3 (CVB3)-induced diseases such as myocarditis and cardiomyopathy. Recent work in CAR-deficient animals has indicated a role in embryonic development and remodeling with cardiac malformation and lethality.Methods We generated a tamoxifen-inducible knockout (KO) mouse to study CAR in the adult heart after CVB3 infection. Histomorphology, virus distribution, and cardiac function were compared in CAR-KO versus noninduced littermate control animals expressing wild-type CAR (WT).Results We have demonstrated that eliminating CAR prevents signs of inflammatory cardiomyopathy, with essentially no pathology in KO hearts. Unlike CVB3-infected WT control animals, the cardiac inducible KO mice did not exhibit structural changes such as monocyte infiltration or fibrosis after CVB3 infection or increased production of markers of inflammation such as interleukin-6 and -10. Whereas CVB3 infection resulted in severe contractile dysfunction in the hearts of animals that express WT, the CAR-deficient hearts appeared normal.Conclusions Elimination of CAR in adult hearts can efficiently block virus entry and the associated pathology including contractile dysfunction. The lack of infiltration or other morphological changes in CVB3-infected KO hearts emphasizes the contribution of direct virus-mediated pathology in enteroviral myocarditis. (J Am Coll Cardiol 2009; 53: 1219-26) (C) 2009 by the American College of Cardiology Foundation