Zhejun Cai1, Li Shen1, Hong Ma1, Jin Yang1, Du Yang1, Han Chen1, Jia Wei1, Qiulun Lu1, Dao Wen Wang1, Meixiang Xiang2, Jian'an Wang2. 1. From the Key Laboratory of Cardiovascular Disease of Zhejiang Province and Department of Cardiology, Second Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, China (Z.C., L.S., H.M., D.Y., H.C., M.X., J. Wang); Department of Medicine, Blood Center of Zhejiang Province, Hangzhou, China (J.Y.); Transform Medical Center, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China (J.Y.); Department of Pediatric Surgery (J. Wei) and Institute of Hypertension and Department of Internal Medicine (D.W.W.), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; and Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China (Q.L.). 2. From the Key Laboratory of Cardiovascular Disease of Zhejiang Province and Department of Cardiology, Second Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, China (Z.C., L.S., H.M., D.Y., H.C., M.X., J. Wang); Department of Medicine, Blood Center of Zhejiang Province, Hangzhou, China (J.Y.); Transform Medical Center, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China (J.Y.); Department of Pediatric Surgery (J. Wei) and Institute of Hypertension and Department of Internal Medicine (D.W.W.), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; and Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China (Q.L.). wja@zju.edu.cn xiangmxhz@163.com.
Abstract
BACKGROUND: This study tested the hypothesis whether endoplasmic reticulum (ER) stress/C/EBP homologous protein (CHOP) signaling is linked with coxsackievirus B3 (CVB3)-induced acute viral myocarditis (AVMC) in vivo. METHODS AND RESULTS: AVMC was induced by intraperitoneal injection of 1000 tissue culture infectious dose (TCID50) of CVB3 virus in mice. In AVMC mouse hearts (n=11), ER stress and CHOP were significantly activated, and were linked to the induction of proapoptotic signaling including reduction of Bcl-2, activation of Bax and caspase 3, compared with the controls (n=10), whereas these could be markedly blocked by ER stress inhibitor tauroursodeoxycholic acid administration (n=11). Moreover, chemical inhibition of ER stress significantly attenuated cardiomyocytes apoptosis, and prevented cardiac troponin I elevation, ameliorated cardiac dysfunction assessed by both hemodynamic and echocardiographic analysis, reduced viral replication, and increased survival rate after CVB3 inoculation. We further discovered that genetic ablation of CHOP (n=10) suppressed cardiac Bcl-2/Bax ratio reduction and caspase 3 activation, and prevented cardiomyotes apoptosis in vivo, compared with wild-type receiving CVB3 inoculation (n=10). Strikingly, CHOP deficiency exhibited dramatic protective effects on cardiac damage, cardiac dysfunction, viral replication, and promoted survival in CVB3-caused AVMC. CONCLUSIONS: Our data imply the involvement of ER stress/CHOP signaling in CVB3-induced AVMC via proapoptotic pathways, and provide a novel strategy for AVMC treatment.
BACKGROUND: This study tested the hypothesis whether endoplasmic reticulum (ER) stress/C/EBP homologous protein (CHOP) signaling is linked with coxsackievirus B3 (CVB3)-induced acute viral myocarditis (AVMC) in vivo. METHODS AND RESULTS:AVMC was induced by intraperitoneal injection of 1000 tissue culture infectious dose (TCID50) of CVB3 virus in mice. In AVMCmouse hearts (n=11), ER stress and CHOP were significantly activated, and were linked to the induction of proapoptotic signaling including reduction of Bcl-2, activation of Bax and caspase 3, compared with the controls (n=10), whereas these could be markedly blocked by ER stress inhibitor tauroursodeoxycholic acid administration (n=11). Moreover, chemical inhibition of ER stress significantly attenuated cardiomyocytes apoptosis, and prevented cardiac troponin I elevation, ameliorated cardiac dysfunction assessed by both hemodynamic and echocardiographic analysis, reduced viral replication, and increased survival rate after CVB3 inoculation. We further discovered that genetic ablation of CHOP (n=10) suppressed cardiac Bcl-2/Bax ratio reduction and caspase 3 activation, and prevented cardiomyotes apoptosis in vivo, compared with wild-type receiving CVB3 inoculation (n=10). Strikingly, CHOP deficiency exhibited dramatic protective effects on cardiac damage, cardiac dysfunction, viral replication, and promoted survival in CVB3-caused AVMC. CONCLUSIONS: Our data imply the involvement of ER stress/CHOP signaling in CVB3-induced AVMC via proapoptotic pathways, and provide a novel strategy for AVMC treatment.
Authors: Remi Villenave; Samantha Q Wales; Tiama Hamkins-Indik; Efstathia Papafragkou; James C Weaver; Thomas C Ferrante; Anthony Bahinski; Christopher A Elkins; Michael Kulka; Donald E Ingber Journal: PLoS One Date: 2017-02-01 Impact factor: 3.240