Effect of verapamil on acute coxsackievirus B3 murine myocarditis.
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The effect of verapamil (Ver) on CVB3 murine myocarditis was investigated. It was found that Ver could aggravate the myocardial inflammation, increase the viral replication in myocardium, and raise mortality in mice with viral myocarditis when the drug was injected within the first 6 days after the CVB3 inoculation.Keywords:
Viral Myocarditis
Coxsackievirus
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Viral myocarditis, which is mainly caused by coxsackievirus B3 (CVB3), affects about 5%-20% of the world population and still lacks efficient treatments. Green tea, a tonic and healthful beverage that was originated in ancient China, has been receiving considerable attention for its protective effect on cardiovascular diseases in recent years. In the present investigation, we aimed to explore the effect of green tea polyphenol epigallocatechin-3-gallate (EGCG) on CVB3-induced myocarditis and its underlying mechanism. Our study showed that EGCG could alleviate CVB3-induced myocarditis as evidenced by less cardiac injury and higher survival rate. Furthermore, we found that EGCG failed to downregulate the expression of inflammatory cytokines but could significantly inhibit the replication of CVB3. Furthermore, we found that EGCG treatment could downregulate the protein expression level of coxsackievirus and adenovirus receptor, the major receptor for CVB3 to infect cardiac myocytes. In conclusion, our data indicated that EGCG could ameliorate CVB3-induced myocarditis through inhibiting viral replication, which might provide a potential novel therapeutic strategy for viral myocarditis.
Viral Myocarditis
Coxsackievirus
Green tea extract
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Background Viral myocarditis, which is most prevalently caused by Coxsackievirus B3 (CVB3) infection, is a serious clinical condition characterized by cardiac inflammation. However, efficient therapies targeting inflammation are still lacking and much needed. A20, also known as tumor necrosis factor alpha induced protein 3 (TNFAIP3) is a key negative regulator of inflammation. But whether A20 may affect cardiac inflammation during acute viral myocarditis remains to be elucidated. The aim of this study was to investigate the potential protective effect of A20 on CVB3-induced myocarditis. Methodology/Principal Findings Mice were intraperitoneally inoculated with CVB3 to establish acute viral myocarditis model. We found that the expression of pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6 and monocyte chemotactic protein-1 (MCP-1) were markedly and persistently increased during the progression of CVB3-induced myocarditis, and positively correlated with the disease severity. Notably, intravenous injection in vivo with adenovirus expressed A20 (Ad-A20) remarkably reduced CVB3-induced pro-inflammatory cytokines production and alleviated the severity of myocarditis. Further, we observed that nuclear factor-kappaB (NF-κB) signaling which mediates inflammatory response was significantly inhibited in CVB3-infected mice with Ad-A20 treatment. Finally, we revealed that A20 was required to inhibit CVB3-induced NF-κB signaling by restricting TNF receptor associated factor 6 (TRAF6) ubiquitylation. Conclusion/Significance This study demonstrates the protective role of A20 against CVB3-induced myocarditis, which may provide a new therapeutic strategy for the treatment of viral myocarditis.
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Myocarditis is a common inflammatory heart disease in children and young adults that may result in chronically dilated cardiomyopathy. Coxsackievirus B3 is the major etiologic agent of this disease. Current treatments for patients with viral myocarditis are almost entirely supportive. In recent years, some promising therapeutic candidates have emerged, including novel treatments and improvements of existing drugs. Among these are molecules that specially target virus entry, such as pleconaril, WIN 54954 and CAR-Fc; nucleic acid-based antiviral agents that inhibit viral translation and/or transcription, such as antisense oligodeoxynucleotide and short interfering RNA; and immunomodulatory agents that augment the host-protective immune responses to effectively clear viruses from target tissues, including interferons and immunoglobulins. In addition, certain new antiviral strategies, still in the early stages, include modulation of signal transduction pathways responsible for viral replication using enzyme inhibitors, which have revealed potential therapeutic targets for viral myocarditis. Finally, the progress in cellular cardiomyoplasty for end-stage therapy, in particular the preliminary clinical trials, is also discussed with respect to its potential future application.
Viral Myocarditis
Coxsackievirus
Dilated Cardiomyopathy
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Myocarditis is an inflammatory disease caused by viral infection. Different subpopulations of leukocytes enter the cardiac tissue and lead to severe cardiac inflammation associated with myocyte loss and remodeling. Here, we study possible cell sources for viral replication using three compartments of the heart: fibroblasts, cardiomyocytes, and macrophages. We infected C57BL/6j mice with Coxsackievirus B3 (CVB3) and detected increased gene expression of anti-inflammatory and antiviral cytokines in the heart. Subsequently, we infected cardiac fibroblasts, cardiomyocytes, and macrophages with CVB3. Due to viral infection, the expression of TNF-α, IL-6, MCP-1, and IFN- β was significantly increased in cardiac fibroblasts compared to cardiomyocytes or macrophages. We found that in addition to cardiomyocytes cardiac fibroblasts were infected by CVB3 and displayed a higher virus replication (132-fold increase) compared to cardiomyocytes (14-fold increase) between 6 and 24 hours after infection. At higher virus concentrations, macrophages are able to reduce the viral copy number. At low virus concentration a persistent virus infection was determined. Therefore, we suggest that cardiac fibroblasts play an important role in the pathology of CVB3-induced myocarditis and are another important contributor of virus replication aggravating myocarditis.
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Dilated Cardiomyopathy
Coxsackievirus
Viral Myocarditis
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Viral myocarditis is caused by infection with viruses or bacteria, including coxsackievirus B3 (CVB3), and is characterized by acute or chronic inflammatory responses in the heart. The mortality associated with severe viral myocarditis is considerable. In some patients, viral myocarditis may develop into dilated cardiomyopathy or heart failure. Autophagy is involved in a wide range of physiological processes, including viral infection and replication. In the present review, we focus on the responses of cardiac tissues, cardiomyocytes, and cardiac fibroblasts to CVB3 infection. Subsequently, the effects of altered autophagy on the development of viral myocarditis are discussed. Finally, this review also examined and assessed the use of several popular autophagy modulating drugs, such as metformin, resveratrol, rapamycin, wortmannin, and 3-methyladenine, as alternative treatment strategies for viral myocarditis.
Viral Myocarditis
Coxsackievirus
Dilated Cardiomyopathy
Wortmannin
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The effect of verapamil (Ver) on CVB3 murine myocarditis was investigated. It was found that Ver could aggravate the myocardial inflammation, increase the viral replication in myocardium, and raise mortality in mice with viral myocarditis when the drug was injected within the first 6 days after the CVB3 inoculation.
Viral Myocarditis
Coxsackievirus
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Viral myocarditis is an inflammatory disease of the heart muscle that can be fatal. The primary viruses that have been linked to myocarditis and dilated cardiomyopathy are the human enteroviruses. The most common viruses associated with this disease are the Coxsackie B viruses and in particular Coxsackievirus B3 and Coxsackievirus B5. Early events in viral infection include attachment of the virus onto cell surface receptors. Even though, CD55 and Coxsackievirus adenovirus receptor protein (CAR) have been identified as receptors for Coxsackievirus B3, the exact mechanisms that Coxsackievirus B3 and B5 use to infect the cardiac muscle are not yet known. In this study, attempts were made to inhibit Coxsackievirus B3 and Coxsackievirus B5 infectivity of cardiac cells by using CAR and CD55 specific antibodies. The results show that these antibodies could not completely inhibit Coxsackievirus B3 and Coxsackievirus B5 binding or infectivity. Furthermore five new proteins have been identified that are used by Coxsackieviruses for binding to cardiac tissue and are distinct from CAR or CD55, leading us to believe that these viruses may use a different set of receptors for infection of cardiac muscle.
Coxsackievirus
Infectivity
Viral Myocarditis
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Myocarditis offers a unique opportunity to study the factors contributing to its transition from a viral infection to an autoimmune disease. In this article, we review recent studies on the role of nitric oxide (NO), gamma interferon (IFN-γ) and interleukin 12 (IL-12) in the progression from early (viral) to late (autoimmune) phases of myocarditis induced by Coxsackievirus B3 (CB3) in highly susceptible (A.CA) and moderately susceptible (B10.M) mice. NO plays a paradoxical role, being protective in early stages but detrimental later in the course of disease. Treatment with antibody to IFN-γ reduced early disease, but had little effect on the severity of cardiac lesions at later times. Treatment with recombinant (r) IL-12 significantly reduced the autoimmune cardiac lesions in moderately susceptible B10.M mice, but had no measurable effect in highly susceptible A.CA animals. These studies provide evidence that the profile of inflammatory mediators produced early in the course of viral infection determines the later development of autoimmune disease.
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Background . Infection with Coxsackievirus B3 induces myocarditis. We aimed to compare the acute and chronic phases of viral myocarditis to identify the immediate effects of cardiac inflammation as well as the long-term effects after resolved inflammation on cardiac fibrosis and consequently on cardiac function. Material and Methods . We infected C57BL/6J mice with Coxsackievirus B3 and determined the hemodynamic function 7 as well as 28 days after infection. Subsequently, we analyzed viral burden and viral replication in the cardiac tissue as well as the expression of cytokines and matrix proteins. Furthermore, cardiac fibroblasts were infected with virus to investigate if viral infection alone induces profibrotic signaling. Results . Severe cardiac inflammation was determined and cardiac fibrosis was consistently colocalized with inflammation during the acute phase of myocarditis. Declined cardiac inflammation but no significantly improved hemodynamic function was observed 28 days after infection. Interestingly, cardiac fibrosis declined to basal levels as well. Both cardiac inflammation and fibrosis were reversible, whereas the hemodynamic function remains impaired after healed viral myocarditis in C57BL/6J mice.
Viral Myocarditis
Cardiac Fibrosis
Myocardial fibrosis
Coxsackievirus
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