title: Involvement of Endoplasmic Reticulum Stress-Mediated C/EBP Homologous Protein Activation in Coxsackievirus B3-Induced Acute Viral Myocarditis.
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.
  
  
  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.
authors.affiliation: 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.).
authors.forename: Zhejun
authors.initials: Z
authors.lastname: Cai
authors.affiliation: 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.).
authors.forename: Li
authors.initials: L
authors.lastname: Shen
authors.affiliation: 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.).
authors.forename: Hong
authors.initials: H
authors.lastname: Ma
authors.affiliation: 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.).
authors.forename: Jin
authors.initials: J
authors.lastname: Yang
authors.affiliation: 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.).
authors.forename: Du
authors.initials: D
authors.lastname: Yang
authors.affiliation: 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.).
authors.forename: Han
authors.initials: H
authors.lastname: Chen
authors.affiliation: 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.).
authors.forename: Jia
authors.initials: J
authors.lastname: Wei
authors.affiliation: 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.).
authors.forename: Qiulun
authors.initials: Q
authors.lastname: Lu
authors.affiliation: 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.).
authors.forename: Dao Wen
authors.initials: DW
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Meixiang
authors.initials: M
authors.lastname: Xiang
authors.affiliation: 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.
authors.forename: Jian'an
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D003384:Coxsackievirus Infections / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control / Q000821:virology; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism* / Q000821:virology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D029822:Enterovirus B, Human / Q000187:drug effects / Q000254:growth & development / Q000472:pathogenicity*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009205:Myocarditis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control / Q000821:virology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology; D051742:Transcription Factor CHOP / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; C494827:Bax protein, mouse; C497250:Ddit3 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C052617:Bcl2 protein, mouse; D051742:Transcription Factor CHOP; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; C505409:Casp3 protein, mouse; D053148:Caspase 3
keywords: C/EBP homologous protein; apoptosis; endoplasmic reticulum stress