taurochenodeoxycholic-acid and Myocarditis

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.. 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.. 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.

Topics: Animals; Antiviral Agents; Apoptosis; bcl-2-Associated X Protein; Caspase 3; Coxsackievirus Infections; Disease Models, Animal; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Enterovirus B, Human; Male; Mice, Inbred C57BL; Mice, Knockout; Myocarditis; Myocytes, Cardiac; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Taurochenodeoxycholic Acid; Transcription Factor CHOP; Virus Replication