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Coxsackievirus B3 Induces Autophagic Response in Cardiac Myocytes in vivo

Xia Zhai1#, Bing Bai2#, Bohai Yu1, Tanying Wang1, Huapeng Wang3, Yao Wang3, Huiyan Li2, Lei Tong1, Yan Wang1, Fengmin Zhang1, Wenran Zhao3*, and Zhaohua Zhong1*

1Department of Microbiology, Harbin Medical University, 194 Xuefu Road, Harbin 150086, China; E-mail: zhonghzh@hrbmu.edu.cn

2Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Harbin 150001, China

3Department of Cell Biology, Harbin Medical University, 194 Xuefu Road, Harbin 150086, China; E-mail: zhaowr@ems.hrbmu.edu.cn; zhaowenran2002@aliyun.com

# These authors contributed equally to this work.

* To whom correspondence should be addressed.

Received November 20, 2014; Revision received February 9, 2015
Viral myocarditis is a common disease that contributes to dilated cardiomyopathy or heart failure. Coxsackievirus B (CVB) is one of the major causative pathogens of viral myocarditis. Previous studies have shown that autophagy is exploited to promote CVB replication in cell lines. To study whether cardiac myocytes respond to CVB infection in a similar way, viral myocarditis was established by the inoculation of 3-week-old BALB/c mice with CVB3. Electron microscopic observation showed that autophagosome-like vesicles were induced in the cardiac myocytes of mice infected by CVB3 at 3, 5, and 7 days after viral infection. The lipidated microtubule-associated protein 1 light chain 3 (LC3), LC3-II, was also significantly increased in both myocardium and the cardiac myocytes extracted from the ventricles of mice infected with CVB3. The increased LC3-II coincided with high level of viral RNA and proteins in both myocardium and isolated cardiac myocytes. Moreover, viral protein synthesis was significantly decreased in primary cardiac myocytes by the treatment with 3-methyladenine, an inhibitor of autophagy. The expression and the phosphorylation of extracellular signal regulated kinase (ERK) were also increased in both myocardium and in the isolated cardiac myocytes of the virus-infected mice, while the interplay of ERK with autophagic response remains to be studied. This study demonstrated that cardiac myocytes respond to CVB3 infection by increased formation of autophagosomes in vivo, which might be exploited for viral replication.
KEY WORDS: coxsackievirus B, cardiac myocytes, myocardium, autophagy, autophagosome

DOI: 10.1134/S0006297915080052