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. Methods and Results— AVMC was induced by intraperitoneal injection of 1000 tissue culture infectious dose (TCID 50 ) 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.

Acupuncture protects against cerebral ischemia–reperfusion injury via suppressing endoplasmic reticulum stress-mediated autophagy and apoptosis

“…ER stress-related caspase 12 and CHOP proteins participate in apoptosis regulation (Kamarehei et al 2019 ). It has been shown that the activation of PERK-eIF2α-ATF4 pathway results in increased CHOP expression that up-regulates Bax/Bcl-2 ratio and finally causes caspase-3 activation (Cai et al 2015 ). Previous research indicated that the activation of ER-specific caspase-12 can trigger the following activation of caspase-9 and caspase-3, which leads to an apoptotic caspase cascade (Kim et al 2019 ).…”

Human Gut-On-A-Chip Supports Polarized Infection of Coxsackie B1 Virus In Vitro

“…CVs are responsible for a broad range of diseases that can be life-threatening in children and neonates; however, little is known about their induced pathogenicity and how they interact with the human gut epithelium, their primary site of infection. While animal models have been used to study the biology and pathogenesis of CV infection [ 24 , 25 ], current murine models largely rely on inoculation into the intraperitoneal space or directly into the brain, and thus, they fail to recapitulate the natural route of infection through the respiratory and intestinal mucosa [ 26 – 28 ]. Recently, a 3D culture model that recapitulates shear stress in the intestine by culturing Caco2 cells on extracellular matrix-coated beads in a rotating wall vessel bioreactor was used to study CVB3 infection [ 29 ].…”

IFN-γ versus IL-17: A Battle During Cardiac Autoimmunity Evolution

“…Cardiomyocyte cellular damage may be induced by infection with pathogens, endogenous stress from mechanical or oxidative traumas, or from mutated proteins ( Figure 1A-C) [19][20][21][22]. These insults promote activation of the innate immune response through pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs) and Nod-like receptors (NLRs).…”