Involvement of Endoplasmic Reticulum Stress–Mediated C/EBP Homologous Protein Activation in Coxsackievirus B3–Induced Acute Viral Myocarditis. (July 2015)

• Record Type: Journal Article
• Authors: Cai, Zhejun; Shen, Li; Ma, Hong; Yang, Jin; Yang, Du; Chen, Han; Wei, Jia; Lu, Qiulun; Wang, Dao Wen; Xiang, Meixiang; Wang, Jian'an
• Is Part Of: Circulation. Volume 8:Number 4(2015)
• Publication Date: 2015-07
• Subjects: Heart failure -- Periodicals; 616.129005
• DOI: 10.1161/CIRCHEARTFAILURE.114.001244
• Languages: English
• ISSNs: 1941-3289

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <title>Background—</title> <p>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.</p> </sec> <sec> <title>Methods and Results—</title> <p>AVMC was induced by intraperitoneal injection of 1000 tissue culture infectious dose (TCID<sub>50</sub>) 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.</p> </sec> <sec> <title>Conclusions—</title> <p>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.</p> </sec> </abstract>