Canadian Journal of Cardiology

Endoplasmic Reticulum Stress Aggravates Viral Myocarditis by Raising Inflammation Through the IRE1-Associated NF-κB Pathway

  • Author Footnotes
    ∗ These authors contributed equally to this work.
    Xi Zha
    ∗ These authors contributed equally to this work.
    Jiangsu Provincial Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Science, Soochow University, Suzhou, People's Republic of China
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  • Author Footnotes
    ∗ These authors contributed equally to this work.
    Yan Yue
    ∗ These authors contributed equally to this work.
    Jiangsu Provincial Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Science, Soochow University, Suzhou, People's Republic of China
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  • Ning Dong
    Jiangsu Provincial Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Science, Soochow University, Suzhou, People's Republic of China
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  • Sidong Xiong
    Corresponding author: Dr Sidong Xiong, 199 Ren-Ai Road, Suzhou, Jiangsu, 215123, PR China. Tel.: 86-512-65881255; fax: 86-512-65881255.
    Jiangsu Provincial Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Science, Soochow University, Suzhou, People's Republic of China
    Search for articles by this author
  • Author Footnotes
    ∗ These authors contributed equally to this work.
Published:March 11, 2015DOI:



      Viral myocarditis, which is mostly caused by coxsackievirus infection, is characterized by myocardial inflammation. Abnormal endoplasmic reticulum (ER) stress participates in many heart diseases, but its role in viral myocarditis remains unsolved.


      We investigated the influence of ER stress in coxsackievirus B3 (CVB3)-induced viral myocarditis by dynamically detecting its activation in CVB3-infected hearts, analyzing its association with myocarditis severity, and exploring its impact on disease development by modulating the strength of ER stress with the chemical activator tunicamycin (Tm) or the inhibitor tauroursodeoxycholic acid (TUDCA). The underlying signal pathway of ER stress in CVB3-induced myocarditis was also deciphered.


      We found that myocardial expression of Grp78 and Grp94, 2 ER stress markers, was significantly increased after CVB3 infection and positively correlated with myocarditis severity. Consistently, Tm-augmented ER stress obviously aggravated myocarditis, as shown by more severe myocardial inflammation, reduced cardiac function, and a lower survival rate, whereas TUDCA decreased ER stress and obviously alleviated myocarditis. This pathologic effect of ER stress could be attributed to increased levels of proinflammatory cytokine (interleukin [IL]-6, IL-12, tumor necrosis factor-alpha, and monocyte chemoattractant protein-1) production through the IRE1-associated nuclear factor-κB (NF-kB) pathway.


      ER stress accentuated CVB3-induced myocardial inflammation through the IRE1-associated NF-κB pathway. This study may help us understand the role of ER stress in viral myocarditis and promote the development of corresponding therapeutic strategies based on manipulating ER stress.



      La myocardite virale, qui est généralement causée par l’infection par le virus Coxsackie B3, est caractérisée par l’inflammation du myocarde. Le stress anormal du réticulum endoplasmique (RE) participe à de nombreuses cardiopathies, mais son rôle dans la myocardite virale n’est pas encore résolu.


      Nous avons examiné l’influence du stress du RE dans la myocardite virale induite par le virus Coxsackie B3 (CVB3) en détectant de manière dynamique son activation dans les cœurs infectés par le CVB3, en analysant son association à la gravité de la myocardite et en explorant ses conséquences sur le développement de la maladie par la modulation de la force du stress du RE à l’activateur chimique, la tunicamycine (Tm) ou à l’inhibiteur, l’acide tauroursodéoxycholique (TUDCA). Nous avons également déchiffré la voie de signalisation sous-jacente du stress du RE dans la myocardite induite par le CVB3.


      Nous avons observé que l’expression myocardique de 2 marqueurs du stress du RE, GRP78 et GRP94, était significativement plus élevée après l’infection par le CVB3 et qu’il corrélait de manière positive avec la gravité de la myocardite. Systématiquement, le stress du RE induit par la Tm aggravait manifestement la myocardite, comme en témoigne l’inflammation myocardique plus grave, la diminution de la fonction cardiaque et le plus faible taux de survie, tandis que le TUDCA diminuait le stress du RE et allégeait manifestement la myocardite. Nous pouvons attribuer ces conséquences pathologiques du stress du RE aux concentrations élevées de la production de cytokines pro-inflammatoires (interleukine [IL]-6, IL-12, facteur de nécrose tumorale alpha et protéine-1 de chimioattraction de monocytes) par la voie d’activation du facteur nucléaire kappa B (NF-kB) associée à la IRE1.


      Le stress du RE accentuait l’inflammation du myocarde induite par le CVB3 par la voie NF-κB associée à la IRE1. Cette étude peut nous aider à comprendre le rôle du stress du RE dans la myocardite virale et favorise le développement de stratégies thérapeutiques correspondantes qui s’appuient sur la manipulation du stress du RE.
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