Enterovirus-related activation of the cardiomyocyte mitochondrial apoptotic pathway in patients with acute myocarditis

Ventéo, Lydie; Bourlet, Thomas; Renois, Fanny; Douche-Aourik, Fatima; Mosnier, Jean‐François; Maison, Geoffroy Lorain De la Grand; Pluot, M; Pozzetto, Bruno; Andréoletti, Laurent

doi:10.1093/eurheartj/ehp489

Cited by 29 publications

(20 citation statements)

References 33 publications

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“…However, experimental 27,28 and clinical studies have shown that virus-induced cardiomyocyte apoptosis also has a deleterious effect on LV function, leading to severe heart failure and, in severe cases, death. [29][30][31] In the present study, EMCV-induced cardiac myocyte apoptosis and caspase 3 cleavage were attenuated in αMHC-MDA5 transgenic mice compared with infected LM controls. The decreased prevalence of apoptosis and caspase 3 cleavage in αMHC-MDA5 mice can be explained, at least in part, by the significantly lower viral loads in the hearts of these mice.…”

Section: Discussionsupporting

confidence: 51%

Cardiac-Specific Overexpression of Melanoma Differentiation–Associated Gene-5 Protects Mice From Lethal Viral Myocarditis

Philip

Bowles

et al. 2013

Circ: Heart Failure

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Background-Viral myocarditis is among the most common causes of heart failure in children and young adults. The RNA helicase melanoma differentiation-associated gene-5 (MDA5) is critical for host antiviral responses against members of the Picornaviridae family, such as encephalomyocarditis virus (EMCV). MDA5-knockout mice are highly susceptible to EMCV infection and develop significant myocardial injury and left ventricular dysfunction. However, the mechanisms by which MDA5 signaling within cardiac myocytes contributes to the host response against viral infection have not been defined. Methods and Results-We generated cardiac-specific MDA5 transgenic (alpha-myosin heavy chain [αMHC]-MDA5) mice. These mice showed increased baseline cardiac expression of antiviral cytokines and increased cellular infiltration but no alterations in cardiac function and structure. αMHC-MDA5 mice were less susceptible to EMCV infection and had a significantly lower cardiac viral load compared with littermate control mice. The severity of myocarditis, prevalence of cardiac myocyte apoptosis, and cleavage of caspase 3 after EMCV infection were attenuated in αMHC-MDA5 mice. Furthermore, αMHC-MDA5 mice were protected against EMCV-induced myocardial dysfunction. Conclusions-Our data suggest that myocardial MDA5 may be a key molecule in protecting the heart from direct viral injury and myocardial dysfunction. (Circ Heart Fail. 2013;6:326-334.)

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Section: Discussionsupporting

confidence: 51%

Cardiac-Specific Overexpression of Melanoma Differentiation–Associated Gene-5 Protects Mice From Lethal Viral Myocarditis

Philip

Bowles

et al. 2013

Circ: Heart Failure

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“…For each patient, a mean number of 2.1 (SD ϭ 1.3; range, 1 to 7) large heart tissue samples were fixed, within 2 h of heart transplantation, in 10% neutral buffered formalin and paraffin embedded for classical histopathological analyses (13). All of these 67 heart tissue samples demonstrated histopathological findings compatible with DCM (14).…”

Section: Patientsmentioning

confidence: 99%

Virus Detection and Semiquantitation in Explanted Heart Tissues of Idiopathic Dilated Cardiomyopathy Adult Patients by Use of PCR Coupled with Mass Spectrometry Analysis

Nguyen¹,

Renois²,

Lévêque³

et al. 2013

J Clin Microbiol

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“…7,9,26 Reports already documented that cardiomyocytes apoptosis occurs and contributes to development and severity of CVB3-induced AVMC. 37,38 About the link between ER stress/CHOP signaling and apoptosis, it suggests that ER stress and its downstream activator CHOP may also be emerged in AVMC development induced by CVB3. Our observation truly confirmed this hypothesis by identifying CHOP activation accompanied with increased cardiomyocytes apoptosis in AVMC hearts.…”

Section: Discussionmentioning

confidence: 99%

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

Cai

Shen

et al. 2015

Circ: Heart Failure

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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.

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Enterovirus-related activation of the cardiomyocyte mitochondrial apoptotic pathway in patients with acute myocarditis

Cited by 29 publications

References 33 publications

Cardiac-Specific Overexpression of Melanoma Differentiation–Associated Gene-5 Protects Mice From Lethal Viral Myocarditis

Cardiac-Specific Overexpression of Melanoma Differentiation–Associated Gene-5 Protects Mice From Lethal Viral Myocarditis

Virus Detection and Semiquantitation in Explanted Heart Tissues of Idiopathic Dilated Cardiomyopathy Adult Patients by Use of PCR Coupled with Mass Spectrometry Analysis

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

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