In vivo characterization of cytokine profiles and viral load during murine cytomegalovirus-induced acute myocarditis
J Trees RitterYajarayma Tang-FeldmanG. Raymond LochheadМарко ЭстрадаStephanie R. LochheadCindy YuAmanda Ashton-SagerDipika TutejaChristian M. LeuteneggerClaire Pomeroy
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Viral Myocarditis
Pathogenesis
Proinflammatory cytokine
Viral myocarditis is a main cause of heart failure in young adults, which characterized by cardiac inflammation and caused by Coxsackievirus B3 (CVB3) infection. However, efficient therapies targeting inflammation and inflammatory response pathway are still elusive. Shenqi Fuzheng injection (SQFZI) is extensively applied in the cardiovascular diseases. But whether SQFZI may affect cardiac inflammation during acute viral myocarditis remains to be elucidated. The purpose of the present study was to investigate the potential protective effect of SQFZI on CVB3-induced myocarditis. Total of 120 mice were intraperitoneally inoculated with CVB3 to establish acute viral myocarditis model. For the CVB3-infected mice model, the body weight, mortality was observed. RT-PCR, western blot and immunohistochemistry methods were selected to detect the TRAF6 expression in myocardial tissues. We found that the expression of TRAF6 mRNA and protein were markedly and persistently increased during the progression of CVB3-induced myocarditis. The serum enzymes activity, including CK, CK-MB, LDH, AST, were also enhanced in CVB3-induced myocardial tissues. Notably, injection with SQFZI remarkably reduced CVB3-induced TRAF6 production and alleviated the severity of myocarditis. This study demonstrates the protective role of SQFZI against CVB3-induced myocarditis, which may explore a new therapeutic strategy for the treatment of viral myocarditis.
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The optimization of viral infection dose in Coxsackievirus-induced murine model of viral myocarditis
To optimize the viral dose to establish Coxsackievirus B3(CVB3)-induced myocarditis murine model in different strains of mice,100TCID50 to 10 000TCID50 doses of CVB3 were intraperitoneally injected into sensitive BALB/c male mice and the non-sensitive C57BL/6mice.The severity of viral myocarditis was assessed by evaluation of weight loss,mortality,myocardial CK-MB level and cardiac pathology.1500TCID50 of CVB3was confirmed to be the best dosage to induce viral myocarditis in sensitive BALB/c male mice;and this virus dose also induced a much weaker but visible myocarditis in C57BL/6mice.Taken together,1500TCID50 dosage of CVB3 was demonstrated to be the best model-establishing dosage in BALB/c mice.Although C57BL/6mice is not a recommended strain for CVB3,1500TCID50 of CVB3still could induce myocarditis in these mice which may facilitate the research of viral myocarditis in most gene-knockout mice.Our data provide a very fundamental and key standard for the establishment of CVB3-viral myocarditis and facilitate the future study of this disease.
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Current therapeutics options for viral myocarditis are unsatisfactory. Melatonin (MLT), a hormone secreted by the pineal gland and other organs, has protective effects on ischemic heart injury. However, the potential therapeutic effect of MLT on viral myocarditis is unknown. In this study, we investigated the protective effect of MLT on viral myocarditis in a mouse model of myocarditis infected with coxsackievirus B3 (CVB3) and explored the probable mechanisms. Mice with CVB3-induced myocarditis displayed inflammatory cell infiltration and interstitial edema. MLT treatment significantly ameliorated the myocardial injuries. In addition, the rate of autophagy changed, although apoptosis was inhibited in mouse hearts following treatment with MLT. These results suggest that MLT has a strong therapeutic effect on acute viral myocarditis, which is associated with changes in autophagy and apoptosis in the heart. Thus, MLT could be a promising novel therapeutic approach against viral myocarditis.
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Objective To establish the model of sudden death in mice with mild viral myocarditis . Methods Mild viral myocarditis model was produced in Balb/c mice by Coxsackie virus B 3. Fatal ventricular arrhythmias in mice with myocarditis were induced by giving mice a small amount of aconitine. Results Mild viral myocarditis model was successfully produced in mice.The rate of ventricular arrhythmias caused by aconitine increased (from 33%,64% to 89%) with the decrease (HRD from 28～36 min -1 ,17～25 min -1 to 8～13 min -1 ) of heart rate dispersion in mice with myocarditis. Conclusion Mild viral myocarditis model is successfully established in mice.The interplay of unstability of myocardial electrophysiology and transient risk factor may be responsible for sudden death in mice with mild viral myocarditis.
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Viral myocarditis occurred after viral invasion of the cardiocytes and followed by the releasing of viral particles and inflammatory cells. Acute viral myocarditis is relatively common phase of the disease cured spontaneously in some cases or leading to sever acute heart failure and cardiac damage ended with chronic heart failure with increased mortality rate. The fully understand mechanism of viral myocarditis is unclear but some hypothesis trying to illustrate the events of the disease.
Regardless of etiological cause, myocarditis is treated depending on disease phase and by following the instructions of Heart Failure Society of America guideline.
This article provides the basic knowledge available in literatures to review some important informations of viral myocarditis, with a special focusing on viral myocarditis caused by coxsackievirus B3 infection.
Viral Myocarditis
Coxsackievirus
Viral infection
Etiology
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To study the diagnostic method of slight viral myocarditis in the field of forensic pathology, slight viral myocarditis model was induced in Balb/c murine by coxsackie virus B3. Organs of hearts, livers, spleens, lungs and kidneys were examined through routine pathological methods. Pathological changes at different levels of these organs were observed. The results indicated that viral myocarditis was a kind of disease with multiple organ alterations and that the pathological observation and comprehensive analysis of multiple organs was one of the useful methods for diagnosing slight viral 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.
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Coxsackievirus
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Viral myocarditis occurred after viral invasion of the cardiocytes and followed by the releasing of viral particles and inflammatory cells. Acute viral myocarditis is relatively common phase of the disease cured spontaneously in some cases or leading to sever acute heart failure and cardiac damage ended with chronic heart failure with increased mortality rate. The fully understand mechanism of viral myocarditis is unclear but some hypothesis trying to illustrate the events of the disease. Regardless of etiological cause, myocarditis is treated depending on disease phase and by following the instructions of Heart Failure Society of America guideline. This article provides the basic knowledge available in literatures to review some important informations of viral myocarditis, with a special focusing on viral myocarditis caused by coxsackievirus B3 infection.
Viral Myocarditis
Coxsackievirus
Viral infection
Etiology
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The participation of microRNAs (miRNAs) in cardiovascular diseases suggests them as potential targets for novel preventive and therapeutic strategies. In this study, the key myocardial miRNA, miR-21, was identified in the murine coxsackievirus B3 (CVB3)-induced myocarditis model and its contribution to disease progression was explored.Myocardial microRNA expression changes in CVB3-infected mice were analyzed by real-time PCR and miR-21 was found to be the miRNA whose expression was significantly reduced. Mice were injected with plasmid encoding miR-21 (pMDH-miR-21) at day 1 post CVB3 infection and myocarditis severity was evaluated 7 days post-infection. The underlying mechanism of miR-21 in viral myocarditis was also investigated.Myocardial miR-21 expression was negatively related to viral myocarditis severity. Recovery of miR-21 expression, by injecting with pMDH-miR-21, significantly relieved CVB3-induced myocarditis as shown by increased body weight, reduced myocardial injury, lowered myocarditis score and increased survival rate. Further study showed that miR-21 could protect myocardial apoptosis by specifically inhibiting its target programmed cell death 4 (PDCD4) expression.miR-21 administration efficiently alleviated CVB3-induced myocarditis by repressing PDCD4-mediated apoptosis. Our study not only helps to better understand the pathogenesis of viral myocarditis, but also proves the potential of miR-21 as a novel therapeutic target for treatment of CVB3-induced myocarditis and other apoptosis-mediated cardiovascular diseases.
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Viral myocarditis is known to be a primary cause of dilated cardiomyopathy (DCM) that can lead to heart failure and sudden cardiac death and is invariably caused by myocardial viral infection following active inflammatory destruction of the myocardium. Although acute viral myocarditis frequently recovers on its own, current chronic myocarditis therapies are unsatisfactory, where the persistence of viral or immunological insults to the heart may play a role. Cellular and mouse experimental models that utilized the most prevalent Coxsackievirus group B type 3 (CVB3) virus infection causing myocarditis have illustrated the pathophysiology of viral myocarditis. In this review, immunological insights into the different stages of development of viral myocarditis were discussed, concentrating on the mechanisms of innate and adaptive immunity in the development of CVB3-induced myocarditis.
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