Pathogenesis Of Viral Myocarditis Research Articles

IL-10-producing B cells attenuate cardiac inflammation by regulating Th1 and Th17 cells in acute viral myocarditis induced by coxsackie virus B3

AimsThis work aimed to evaluate the regulatory function of IL-10-producing B cells in viral myocarditis (VMC). Main methodsWe adoptively transferred purified IL-10-producing B cells to VMC mice via the tail vein. We observed the inflammatory responses and cardiac lesions by histological analysis, examined the proportions of spleen Th1 and T17 cells by flow cytometry and expression levels of related transcription factors (T-bet and RORγt) by reverse transcription polymerase chain reaction (RT-PCR), and calculated the cardiac pathological scores and the mean survival times. Key findingsIL-10-producing B cells were found to be T cell-dependent in the pathogenesis of VMC. They mainly downregulated T-bet and RORγt mRNA levels to decrease the proportions of Th1 and Th17 cells, thereby restraining the inflammation and damage in the myocardium in B cell-deficient VMC mice. Adoptive transfer of IL-10-producing B cells before VMC induction also normalized the inflammatory responses and prolonged the survival time in wild-type (WT) VMC mice. While the transfer of IL-10-producing B cells on day 3 of VMC alleviated the severity of disease, it did not extend the mean survival time of VMC mice. By contrast, IL-10-producing B cells showed no effect on day 7 of VMC. In conclusion, IL-10-producing B cells downregulate the proportion of Th1 and Th17 cells to alleviate inflammatory damage in the myocardium during VMC before the induction or the early phase of disease. SignificanceThese findings suggest that IL-10-producing B cells may be a new therapeutic target for modulating the immune response in VMC.

MicroRNA-34a aggravates coxsackievirus B3-induced apoptosis of cardiomyocytes through the SIRT1-p53 pathway.

Viral myocarditis is inflammation of the myocardium mainly caused by a viral infection, and coxsackievirus B3 (CVB3) infection is one of the most common. It is well known that cardiomyocyte apoptosis is involved in the pathogenesis of viral myocarditis. microRNAs (miRNAs, miRs) are endogenous noncoding oligoribonucleotides involved in various pathological conditions, and miR-34a is one of the miRNAs causing apoptosis. Whether miR-34a participates in cardiomyocyte apoptosis during CVB3 infection and the underlying mechanisms is still unclear. In this in vitro study, we found that miR-34a expression increased in cardiomyocytes after CVB3 infection. Furthermore, we found that CVB3 infection augmented histone deacetylase 1 (HDAC1) and Bax expression while inhibiting sirtuin 1 (SIRT1) and Bcl-2 expression, along with the acetylated p53 (Ac-p53) upregulation in cardiomyocytes. The above-mentioned phenomenon was reversed by a miR-34a inhibitor after CVB3 infection. In addition, the Ac-p53 amount increased in CVB3-infected cardiomyocytes, and SRT1720 and trichostatin A (TSA) pretreatment decreased Ac-p53 levels. After pifithrin-α pretreatment of CVB3-infected cardiomyocytes, the protein expression level of HDAC1 decreased while that of SIRT1 increased. Moreover, miR-34a expression and CVB3-induced apoptosis of cardiomyocytes were attenuated by pretreatment with SRT1720, TSA, or pifithrin-α, accompanied with Bax downregulation and Bcl-2 upregulation. In summary, these data indicate that miR-34a induces cardiomyocyte apoptosis by downregulating SIRT1, and the activation of the SIRT1-p53 pathway contributes to CVB3-induced apoptosis of cardiomyocytes. Thus, miR-34a might serve as a potential therapeutic target because it promotes cardiomyocyte apoptosis through the SIRT1-p53 signaling pathway.

Differential Expression of NRG1‐ERBB4‐PSEN1‐NUP98 (NEPN) Signaling Axis as Potential Blood‐Based Biomarkers for Viral Myocarditis

BackgroundMyocarditis, inflammation of the myocardium, is a leading cause of unexpected heart failure in young adults, commonly attributable to viral infections. Myocarditis manifests in a wide range of clinical presentations, from asymptomatic to acute heart failure. The current gold standard for diagnosis relies upon invasive endomyocardial biopsy, requiring histopathological demonstration of inflammation with/without associated myocyte damage. Under these guidelines, diagnostic sensitivity in independent published studies is <30%. We have previously demonstrated that detection of biomarkers within the NEPN pathway (implicated in immune response and heart failure) significantly improved diagnostic sensitivity to ~80%, however, this approach still relies upon biopsy. Thus, in the present study, our aim is to develop a non‐invasive, blood‐based diagnostic assay for viral myocarditis by examining the NEPN signaling axis and their cleavage fragments during the evolution of myocarditis.DesignHeLa cells and human induced pluripotent stem cell (iPSC)‐derived cardiomyocytes (CM) were CVB3‐ or sham‐infected. Western blot analysis and confocal microscopy were performed to determine the expression and subcellular localization of NEPN signaling axis proteins in tissue culture. In addition, tissue and blood from murine models of viral myocarditis (A/J and C57BL/6 mice) were collected at 4 dpi (viremic phase) and 5 to 8 dpi (acute phase), and were analyzed by Western blot analysis, IHC and IF to detect protein expression.ResultsNEPN proteins all show changes in expression and subcellular localization throughout the infection time course. NUP98 is upregulated and cleaved during infection. NRG1 is upregulated in both lysates and supernatants. ERBB4 co‐localizes at the cell membrane with the protease PSEN1. ERBB4 and NRG1 cleavage fragments are secreted and detected in both tissue culture supernatant and mouse plasma. In the plasma of the less susceptible C57BL/6 mice, ERBB4 and NRG1 cleavage fragments increase throughout the viremic and acute phases. However, in the highly susceptible A/J mice, ERBB4 and NRG1 cleavage fragments were not detected in the plasma until 6 dpi (acute phase), when they are highly upregulated as compared to C57BL/6 mice (p=0.001).ConclusionDifferential expression, subcellular localization and cleavage fragments of NEPN signaling axis proteins were detected during the pathogenesis of viral myocarditis. These composite changes may be useful in the development of a blood‐based diagnostic.Support or Funding InformationDr. Hanson's research is supported by the Myocarditis Foundation and Michael Smith Foundation for Health ResearchThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Altered exosomal miR-181d and miR-30a related to the pathogenesis of CVB3 induced myocarditis by targeting SOCS3.

MicroRNAs are a group of gene expression regulators and some of which have been confirmed to be associated with acute viral myocarditis (VM). This study aims to find new biomarkers for VM diagnosis and explore the roles of miRNAs during the pathogenesis of VM. 23 patients with acute myocarditis and 12 controls were included in this research. The expression of 10 candidate miRNAs in the serum exosome was examined by qRT-PCR. The direct targets were predicted using bioinformatics tools and then confirmed by dual luciferase assay and immunoblotting. Levels IL-6 of cell culture supernatants were determined by enzyme-linked immunosorbent assay. Six weeks old male mice were injected intraperitoneally with Coxsackievirus B3 (CVB3) and then treated by miRNA inhibitors through tail vein injection. Five miRNAs were found to have disturbed expression in the exosome and may have the potential to be used as biomarker for VM diagnosis. Meanwhile, the expression of miR-30a and -181d was also altered in the cells after CVB3 infection. We identified SOCS3 as a direct target of miR-30a and -181d. Furthermore, during CVB3 infection, up-regulated miR-30a and -181d are related to enhanced IL-6 level via modulating SOCS3 expression. miRNA inhibitors injection increased mice survival rate after CVB3 infection. miR-30a and -181d contribute to the over-activated inflammatory response to viral infection of the heart during coxsackievirus infection.

Expression of CD80 and CD86 on B cells during coxsackievirus B3-induced acute myocarditis.

IntroductionThe pathogenesis of viral myocarditis (VMC) is unclear, but many studies have shown that VMC is associated with an excessive immune response. CD80 and CD86 are important costimulatory molecules that play a critical role in autoimmunity. However, whether CD80+/CD86+ B cells participate in the pathogenesis of acute VMC is unknown.Material and methodsMale C57BL/6 mice were infected by intraperitoneal injection with coxsackievirus B3 (CVB3) to establish a VMC model. Control mice were administered phosphate-buffered saline intraperitoneally. At one week and two weeks post injection, histopathological changes in heart tissue were assessed with haematoxylin and eosin staining. The frequency of splenic CD80+/CD86+ B cells was measured with flow cytometry.ResultsThe frequency of CD80+ B cells was significantly increased in VMC, while the frequency of CD86+ B cells was significantly decreased. Furthermore, the frequency of CD80+ B cells related to the severity of VMC.ConclusionsThese data show that CD80+/CD86+B cells are involved in the pathogenesis of VMC, with CD80+B cells being more important than CD86+B cells.

PSEN1 and NUP98 as Diagnostic Biomarkers for Human Myocarditis

BackgroundMyocarditis, inflammation of the myocardium not associated with ischemia, is a spectrum of conditions causing considerable morbidity and mortality. The etiologies known to drive such inflammation are diverse and include autoimmunity and drug hypersensitivity, but are most commonly attributed to cardiotropic viral infections. Clinical symptoms are also variable, ranging from life threatening acute illness to chronic disease, while others never come to clinical attention. Moreover, these factors make the frequency of myocarditis difficult to ascertain, however, an estimated 9% of adult autopsies show myocarditis on histologic examination. Given the tools presently available, clinical, etiologic and hitstologic variability make diagnosis, and therefore treatment, exceedingly difficult. The current gold standard of diagnosis is inflammation shown on endomyocardial biopsy with (“active”) or without (“borderline”) myocyte damage. However, under these criteria, myocarditis diagnostic sensitivity is estimated as low as 30%. To improve upon this, we examined several markers implicated in the pathogenesis of viral myocarditis in animal models as possible adjunct diagnostic biomarkers in human myocarditis. PSEN1, a cellular protease implicated in heart failure and NUP98, a nuclear pore protein with inducible cardioprotective and antiviral gene transcription capabilities, have emerged as promising candidates.DesignTwo groups were examined for PSEN1 and NUP98 immunohistochemical (IHC) staining: a development set of 50 cases (18 lymphocytic active or healing myocarditis, 4 eosinophilic myocarditis, 4 idiopathic dilated cardiomyopathy, 3 hypertrophic cardiomyopathy, 4 sarcoidosis, 3 transplant rejection, 1 toxoplasmosis, 4 arrhythmogenic right ventricular cardiomyopathy (ARVC), 4 coronary artery disease (CAD) and 5 normal controls) and a validation set of all (62) cardiac biopsies performed at SPH from January 2015–June 2016, irrespective of diagnosis. Staining intensity was assessed by computer aided image analysis. Statistical analysis was performed using Mann Whitney U test and receiver operating characteristic (ROC) curves. All protocols were approved by the UBC/PHCRI Research Ethics Board.ResultsPSEN1 distinguished myocarditis from all other diagnoses in the development set (p=0.0001). NUP98 could distinguish inflammatory myocarditides as well as viral from non‐viral from most other diagnoses in the development set (p=0.001). ROC values comparing myocarditis to all other cardiomyopathies was 0.85 for PSEN1 and 0.80 for NUP98. These findings appear hold true in preliminary analyses of the validation set.ConclusionPSEN1 and NUP98 appear to be valuable biomarkers, particularly in combination, for improving sensitivity of endomyocardial biopsy for diagnosing myocarditis, and may provide greater ability to deduce etiologic information from such biopsies. Moreover, PSEN1 and NUP98 are detectable even in regions even without inflammation and in tissue long after initial insult. These insights will aid in personalization of treatment and significantly improve clinical outcomes.Support or Funding InformationThis research is funded by the Providence Health Care Research Institute and through donations made to the St. Paul's Hospital Foundation.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Role of gene polymorphisms/haplotypes and serum levels of interleukin-17A in susceptibility to viral myocarditis

Interleukin-17A (IL-17A) has been implicated in the pathogenesis of viral myocarditis (VMC). However, the role of IL-17A polymorphisms in susceptibility to VMC has not been reported to date. The aim of this study was to explore the association between IL-17A variants as well as serum IL-17 levels with VMC. Three single-nucleotide polymorphisms (SNPs) (rs2275913, rs3819025, and rs3748067) were analyzed by the polymerase chain reaction-restriction fragment length polymorphism method in 236 VMC patients and 259 controls from China. Serum IL-17A levels were measured by enzyme-linked immunosorbent assay kits. Multivariable logistic regression analysis that the rs2275913 AA genotype and the haplotype -197A/+45G/+1249G (AGG) were associated with an increased risk of VMC (all P < 0.05). Consistent with these findings, the rs2275913 AA genotype was linked to higher serum IL-17A compared to GG/AG genotype (all P < 0.001). We observed no associations between the other two SNPs and risk of VMC. Serum IL-17A levels were significantly higher in the VMC group than controls (P < 0.001) and gradually increased with the increase of New York Heart Association grade in VMC patients (P < 0.05). Spearman correlation test revealed that the serum IL-17A level was correlated with the cardiac damage and left ventricular systolic functions among VMC patients (all P < 0.05). Our study reveals that IL-17A expression may contribute to the development and severity of VMC. The SNP rs2275913 in the IL-17A gene might exert influence on susceptibility to VMC via linking with the serum IL-17A level.

Study progress of role of Toll-like receptor 9 in pathogenesis of viral myocarditis

Toll-like receptors represents the first line of defense against foreign pathogens and play an essential role in the innate immune response.Toll-like receptor 9(TLR9) is a major receptor mediating CpG DNA signal transduction, which can not only resist inflammation but also induce inflammatory damage.Studies show that the activation of TLR9 which mediated by endogenous nucleic acid released during viral myocarditis (VMC) can cause the heart damage and be involved in the process of VMC.Further study on the role of TLR9 signal in VMC will provide a theoretical foundation for further revealing the pathogenesis of VMC and seeking effective treatment. Key words: Toll-like receptor 9; Myocarditis; Treatment

Phosphorylation and degradation of αB-crystallin during enterovirus infection facilitates viral replication and induces viral pathogenesis.

Protein quality control (PQC) plays a key role in maintaining cardiomyocyte function and homeostasis, and malfunction in PQC is implicated in various forms of heart diseases. Molecular chaperones serve as the primary checkpoint for PQC; however, their roles in the pathogenesis of viral myocarditis, an inflammation of the myocardium caused by viral infection, are largely unknown. AlphaB-crystallin (CryAB) is the most abundant chaperone protein in the heart. It interacts with desmin and cytoplasmic actin to prevent protein misfolding and aggregation and to help maintain cytoskeletal integrity and cardiac function. Here we showed that coxsackievirus infection induced desminopathy-like phenotype of the myocardium, as characterized by the accumulation of protein aggregates and the disruption of desmin organization. We further demonstrated that CryAB was phosphorylated during early and downregulated at later stages of infection. Moreover, we showed that phosphorylated CryAB had a shorter half-life and was targeted to the ubiquitin-proteasome system for degradation. Lastly, we found that overexpression of CryAB significantly attenuated viral protein production and progeny release, indicating an anti-viral function for CryAB. Together, our results suggest a mechanism by which coxsackieviral infection induces CryAB degradation and loss-of-function, resulting in desmin aggregation, ultimately contributing to compromised cytoskeletal integrity and viral cardiomyopathy.

Interleukin-13 reduces cardiac injury and prevents heart dysfunction in viral myocarditis via enhanced M2 macrophage polarization

Viral myocarditis is one of the major causes of congestive heart failure and dilated cardiomyopathy. Recent reports have demonstrated an essential role of cytokines, like interleukin-13 (IL-13), in the pathogenesis of viral myocarditis, while the underlying mechanisms remain poorly defined. Here, using a coxsackie virus B3 (CVB3)-infection model in BALB/C mice, we showed that IL-13 protected mouse heart function in viral myocarditis, seemingly through reduction in T lymphocyte immunity and induction of M2 macrophage polarization. Adoptive transfer to M2 macrophages mimicked the effects of IL-13 on protection from myocarditis, suggesting that the effects of IL-13 may be primarily through regulation of macrophage polarization. Together, our data suggest that application of IL-13 treatment may reduce cardiac Injury and protect heart function in viral myocarditis via enhanced M2 macrophage polarization.

Right Cervical Vagotomy Aggravates Viral Myocarditis in Mice Via the Cholinergic Anti-inflammatory Pathway.

The autonomic nervous system dysfunction with increased sympathetic activity and withdrawal of vagal activity may play an important role in the pathogenesis of viral myocarditis. The vagus nerve can modulate the immune response and control inflammation through a ‘cholinergic anti-inflammatory pathway’ dependent on the α7-nicotinic acetylcholine receptor (α7nAChR). Although the role of β-adrenergic stimulation on viral myocarditis has been investigated in our pervious studies, the direct effect of vagal tone in this setting has not been yet studied. Therefore, in the present study, we investigated the effects of cervical vagotomy in a murine model of viral myocarditis. In a coxsackievirus B3 murine myocarditis model (Balb/c), effects of right cervical vagotomy and nAChR agonist nicotine on echocardiography, myocardial histopathology, viral RNA, and proinflammatory cytokine levels were studied. We found that right cervical vagotomy inhibited the cholinergic anti-inflammatory pathway, aggravated myocardial lesions, up-regulated the expression of TNF-α, IL-1β, and IL-6, and worsened the impaired left ventricular function in murine viral myocarditis, and these changes were reversed by co-treatment with nicotine by activating the cholinergic anti-inflammatory pathway. These results indicate that vagal nerve plays an important role in mediating the anti-inflammatory effect in viral myocarditis, and that cholinergic stimulation with nicotine also plays its peripheral anti-inflammatory role relying on α7nAChR, without requirement for the integrity of vagal nerve in the model. The findings suggest that vagus nerve stimulation mediated inhibition of the inflammatory processes likely provide important benefits in myocarditis treatment.

Effects of the MAPK pathway and the expression of CAR in a murine model of viral myocarditis.

The pathogenesis of viral myocarditis (VMC) is not fully understood. This study aimed to examine the relationship between coxsackie-adenovirus receptor (CAR) and the p38 mitogen activated protein kinase (MAPK) pathway mechanisms in a mouse model. Three groups of mice were established: 5 mice in a control group injected with saline, 15 in the model group injected with coxsackie virus B3 (CVB) and 15 in the intervention group injected with CVB3 but treated with the p38 MAPK inhibitor SB203580. Mice were sacrificed at days 1, 5, 10, 15 and 30 and cardiac tissues were isolated to perform the tests. Quantitative PCR and western blot analysis showed CAR mRNA and protein expression levels were highest in the model group at all time-points (P<0.05). The expression levels of p38 MAPK protein by western blot analysis at days 1, 5 and 10 were obviously higher in the model group (P>0.05). H&E staining used to observe myocardial pathological changes showed the inflammatory infiltration was also higher in the model group at all the time-points (P<0.05). Our results show a direct relationship between CAR and p38 MAPK levels, and since the p38 MAPK inhibitor treatment resulted in reduced levels of CAR as well as lower inflammatory infiltration, it is possible that the signaling pathway may mediate CAR expression during the pathogenesis of VMC.

A review on viral myocarditis-related viruses and pathogenesis

Viral myocarditis (VM) refers to human infections thermophilic myocardium virus that causes the circumscribed or diffuse myocardium-inflammatory lesion. Myocarditis can be caused by a variety of microbial infections, and VM is the most common one. In order to make the medical staff in clinical work have a more in-depth understanding of VM, this paper describes the common rviruses related, VM and its pathogenesis, process. At present, there is no effective drug and treatment method for VM. It is particularly important to further study the pathogenesis of VM on the role of the virus in, and inhibit its role in the further exploration of clinical therapeutic targets, to improve the quality of life of patients with VM and prolong the survival time is of great significance. Studying in-depth virus in the pathogenesis of VM and restraining its function are particularly important for the further exploration of clinical therapeutic targets. It is significant to improve the life quality and prolong the survival time for VM patients. Key words: Myocarditis/VI/ET; Review

Research progress of the pathogenesis of viral myocarditis

The pathogenesis of viral myocarditis is still not completely clear all over the world now.However, the damage to the body caused by the viral myocarditis has been highlighted and its pathogenesis has become a research hot spot.With the development of immunology and molecular biology, the pathogenesis of viral myocarditis has made great breakthrough.Many scholars advocate that the course of viral myocarditis should be divided into three phases: viral replication, immune response and inflammatory dilated cardiomyopathy.This review summarizes the progress of the pathogenesis of viral myocarditis from the above three phases through reviewing previous articles, aiming to provide new evidence and references for clinical diagnosis and therapy of viral myocarditis. Key words: Viral myocarditis; Pathogenesis

Fas-FasL expression and myocardial cell apoptosis in patients with viral myocarditis.

The aim of the current study was to investigate Fas and FasL expression and myocardial cell apoptosis in viral myocarditis patients. Human heart specimens were selected from patients who were autopsied between February 2012 and February 2015; of these, 25 patients were diagnosed with viral myocarditis. Another 15 cases with no diagnosis of myocarditis were selected for the control group. All tissue specimens were divided into two parts, one for reverse transcription-polymerase chain reaction analysis and the other for immunohistochemical and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) analyses. In situ detection of apoptosis was performed by the TUNEL method, which revealed that myocardial cells from the viral myocarditis group exhibited significant apoptosis, whereas no apoptotic cells were observed in the control group. The number of cells staining positive for Fas and FasL protein in the viral myocarditis group was significantly higher than that in the control group (P < 0.05). There was also a correlation between Fas and FasL protein expression levels and scores (r = 0.92, P < 0.05). The mRNA expression of Fas and FasL was significantly higher in the viral myocarditis group than in the control group (P < 0.05). In conclusion, the Fas-FasL system may be involved in the pathogenesis of viral myocarditis. Furthermore, cytotoxic T lymphocytes may mediate cardiac muscle cells apoptosis via Fas-FasL signaling, and thus participate in the pathogenesis of viral myocarditis.

Progresses of the correlation between viral myocarditis and genetic polymorphisms in children

The pathogenesis of viral myocarditis(VMC)still remains uncertain.The direct viral damage to heart muscle cells, the autoimmunity induced by viruses, the gene polymorphism and the genentic susceptibility are involved.Moreover, the symptoms and the prognosis of VMC are various.The relationship between VMC and the relevant gene polymorphism are reviewed in this paper, including coxsackie-adenovirus receptor, vitamin D receptor, human leukocyte antigen, nitric oxide synthase, matrix metalloproteinases, angiotensin converting enzyme and various cytokine.The purpose is to find new breakthroughs on VMC prevention and treatment. Key words: Viral myocarditis; Gene polymorphism; Coxsackie-adenovirus receptor; Vitamin D receptor; Human leukocyte antigen; Cytokines

Macrophages and galectin 3 play critical roles in CVB3-induced murine acute myocarditis and chronic fibrosis

Macrophage influx and galectin 3 production have been suggested as major players driving acute inflammation and chronic fibrosis in many diseases. However, their involvement in the pathogenesis of viral myocarditis and subsequent cardiomyopathy are unknown. Our aim was to characterise the role of macrophages and galectin 3 on survival, clinical course, viral burden, acute pathology, and chronic fibrosis in coxsackievirus B3 (CVB3)-induced myocarditis. Our results showed that C3H/HeJ mice infected with CVB3 and depleted of macrophages by liposome-encapsulated clodronate treatment compared with infected untreated mice presented higher viral titres but reduced acute myocarditis and chronic fibrosis, compared with untreated infected mice. Increased galectin 3 transcriptional and translational expression levels correlated with CVB3 infection in macrophages and in non-depleted mice. Disruption of the galectin 3 gene did not affect viral titres but reduced acute myocarditis and chronic fibrosis compared with C57BL/6J wild-type mice. Similar results were observed after pharmacological inhibition of galectin 3 with N-acetyl-d-lactosamine in C3H/HeJ mice. Our results showed a critical role of macrophages and their galectin 3 in controlling acute viral-induced cardiac injury and the subsequent fibrosis. Moreover, the fact that pharmacological inhibition of galectin 3 induced similar results to macrophage depletion regarding the degree of acute cardiac inflammation and chronic fibrosis opens up the possibility of new pharmacological strategies for viral myocarditis.

Advances in the Traditional Chinese Medicine-Based Management of Viral Myocarditis.

Viral myocarditis (VMC) is a common clinical condition; however, no specific treatment has been available from the perspective of modern western medicine, and typically only symptomatic treatment is provided in clinical settings. The traditional Chinese medicine (TCM) has shown certain advantages in treating VMC. Last few years have witnessed certain advances in the TCM-based research on the etiology and pathogenesis of VMC and its clinical management. This article reviews the clinical advances made in the TCM-based management of VMC in the last 5years.

Involvement of NLRP3 inflammasome in CVB3-induced viral myocarditis.

Viral myocarditis, which is most prevalently caused by coxsackievirus B3 (CVB3) infection, is a serious clinical condition characterized by cardiac inflammation. Inflammasome plays an essential role in the regulation of diverse inflammatory responses by serving as a platform for caspase-1 activation and caspase-1-dependent proteolytic maturation and secretion of IL-1β. Although inflammasome has been reported to be crucial for the development of many inflammatory diseases, its role in the pathogenesis of viral myocarditis is still elusive. The present study aims to investigate whether CVB3 infection activates inflammasome and whether the activation of inflammasome contributes to CVB3-induced myocarditis. Our results showed that CVB3 infection induced inflammasome activation both in vitro and in vivo. With the inhibition of inflammasome activation, the severity of CVB3-induced myocarditis was significantly alleviated as evidenced by less weight loss, decreased serological indexes of creatine kinase and creatinekinase-MB activities, as well as less severe myocardial injury. Of importance, echocardiography results showed that inhibition of inflammasome activation also efficiently improved cardiac function as revealed by enhanced left ventricular ejection fraction and left ventricular fractional shortening. Despite that CVB3 infection significantly increased the expression of both retinoic acid-inducible gene 1 and NOD-like receptor family, pyrin domain containing 3 (NLRP3) in cardiac myocytes, CVB3-induced inflammasome activation was NLRP3-, but not retinoic acid-inducible gene 1, dependent. Further study showed that reactive oxygen species production and K(+) efflux were critical for the activation of NLRP3 inflammasome upon CVB3 infection. Collectively, our study demonstrated a crucial role of the NLRP3 inflammasome in the pathogenesis of CVB3-induced myocarditis, and modulation of inflammasome activation might represent a promising therapeutic strategy for viral myocarditis.

Expression and significance of myocardial interleukin-17A in mice with viral myocarditis

Objective To explore the expression of interleukin-17A(IL-17A) in the myocardium of mice with experimental viral myocarditis(VM) and its clinical significance. Methods Fifty-five mice were randomly divided into myocarditis group(n=45) and control group(n=10). Mice in the myocarditis group were inoculated intraperitoneally with 0.1 mL Eagle's solution containing coxsackievirus B3(CVB3) to establish VM models.However, mice in the control mice were treated with 0.1 mL Eagle's solution.Ten infected mice were sacrificed on day 7, 14 and 28 after inoculation, and the control mice were killed on day 28 postinoculation.Myocardial histopathology was determined with hematoxylin and eosin stain.The levels of myocardial IL-17A mRNA and protein expressions were detected by real time quantitative polymerase chain reaction(RQ-PCR) and immunohistochemistry.Serum IL-17A concentration was examined using enzyme linked immunosorbent assay(ELISA). In addition, the relationship between myocardial IL-17A protein levels as well as serum IL-17A concentration and myocardial histopathological scores were analyzed statistically in myocarditis group. Results The levels of myocardial IL-17A mRNA and protein and serum IL-17A concentration on day 7 and 14 after inoculation in myocarditis group increased significantly compared with those in control group(all P<0.01). Myocardial IL-17A protein levels and serum IL-17A concentration showed significantly positive correlation with the myocardial histopathologic scores in VM group, respectively(r=0.67, 0.74, all P<0.05). Conclusions IL-17A may play a pivotal role in the pathogenesis of VM and is associated with the severity of VM.It can serve as a novel indicator for VM. Key words: Interleukin-17A; Viral myocarditis; Coxsackievirus B3