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Endoplasmic Reticulum Stress Aggravates Viral Myocarditis by Raising Inflammation Through the IRE1-Associated NF-κB
1Jiangsu Provincial Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Science, Soochow University, Suzhou, People's Republic of China.
Insights
Endoplasmic reticulum (ER) stress exacerbates viral myocarditis by increasing inflammation via the IRE1-associated NF-κB pathway. Targeting ER stress may offer new therapeutic strategies for this heart condition.
Area of Science:
- Cardiology
- Molecular Biology
- Virology
Background:
- Viral myocarditis involves myocardial inflammation, often caused by coxsackievirus.
- The role of abnormal endoplasmic reticulum (ER) stress in viral myocarditis is not well understood.
Purpose of the Study:
- To investigate the influence of ER stress in coxsackievirus B3 (CVB3)-induced viral myocarditis.
- To analyze the association between ER stress and myocarditis severity.
- To explore the underlying signaling pathway of ER stress in CVB3-induced myocarditis.
Main Methods:
- Detected ER stress activation in CVB3-infected hearts.
- Modulated ER stress using tunicamycin (Tm) or tauroursodeoxycholic acid (TUDCA).
- Deciphered the signal pathway involving IRE1 and nuclear factor-κB (NF-κB).
Main Results:
- Increased myocardial expression of ER stress markers (Grp78, Grp94) correlated with myocarditis severity.
- Tunicamycin aggravated myocarditis, while tauroursodeoxycholic acid alleviated it.
- ER stress increased proinflammatory cytokine production via the IRE1-associated NF-κB pathway.
Conclusions:
- Endoplasmic reticulum stress accentuates CVB3-induced myocardial inflammation through the IRE1-associated NF-κB pathway.
- Findings suggest ER stress modulation as a potential therapeutic strategy for viral myocarditis.
Background:
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.
Methods:
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.
Results:
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.
Conclusions:
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.
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