Corrigendum: Ivabradine Treatment Reduces Cardiomyocyte Apoptosis in a Murine Model of Chronic Viral Myocarditis.

[This corrects the article DOI: 10.3389/fphar.2018.00182.].

IDO1 depletion induces an anti-inflammatory response in macrophages in mice with chronic viral myocarditis.

Inflammation and myocardial weakness, two major hallmarks of chronic viral myocarditis (VMC), often lead to dilated cardiomyopathy or chronic heart failure. It has been reported that indoleamine 2,3-dioxygenase-1 (IDO1) may play a pathogenic role in the progression of inflammatory diseases. Hence, the study is set out to investigate the potential role of IDO1 in chronic VMC by establishing a mouse model of VMC by intraperitoneally injected with coxsackievirus B3 (CVB3). After model establishment, the expression of IDO1 was determined by RT-qPCR and Western blot analysis. IDO1 was identified as an up-regulated gene in CVB3-induced VMC. Then, in order to elucidate the potential role of IDO1 in VMC, macrophages were isolated and treated with the overexpression plasmid of IDO1 or IDO1 inhibitor (1-MT). After that, these transfected macrophages were co-cultured with normal cardiomyocytes, followed by measurement of inflammatory factors and evaluation of cardiomyocyte injury. The overexpression of IDO1 was observed to significantly enhance the levels of interleukin (IL)-6, IL-1ß and tumor necrosis factor-α (TNF-α), as well as lactate dehydrogenase (LDH) activity and malondialdehyde (MDA) content. By contrast, the treatment of 1-MT in macrophages reversed the promoting effects of IDO1 on cardiomyocyte injury. Co-culture experiment showed that overexpressed IDO1 impaired cardiomyocyte, which was alleviated upon treatment of 1-MT. Taken together, the key findings of the present study provide evidence that 1-MT-mediated IDO1 suppression could potentially reduce inflammatory response in macrophages and consequently ameliorate cardiomyocyte injury in mice with VMC.

Ivabradine Treatment Reduces Cardiomyocyte Apoptosis in a Murine Model of Chronic Viral Myocarditis.

This study was designed to explore the effects of ivabradine on cardiomyocyte apoptosis in a murine model of chronic viral myocarditis (CVMC). Mice were inoculated intraperitoneally with Coxsackievirus B3 at days 1, 14, and 28, respectively. On day 42, the mice were gavaged with ivabradine for 30 days until the 72nd day. The heart of infected mice was dilated and a large number of interstitial fibroblasts infiltrated into the myocardium on day 42. Compared with the untreated CVMC mice, mice treated with ivabradine showed a significant reduction in heart rate and less impairment of left ventricular function on day 72. The positive apoptosis of myocardial cells in the untreated CVMC group was significantly higher than that of the normal group and was significantly reduced after treatment with ivabradine. The expression levels of Bax and Caspase-3 in the untreated CVMC group were significantly higher than those of the normal group and were apparently reduced in the ivabradine-treated group versus the untreated CVMC group. Bcl-2 showed a high expression in the normal group and low expression in the untreated CVMC group, but its expression level in the ivabradine-treated group were higher than that of the untreated CVMC group. These results indicate that ivabradine could attenuate the expression of Caspase-3 by downregulation of Bax and upregulation of Bcl-2 to prevent the deterioration of cardiac function resulting from ventricular myocyte loss by cardiomyocyte apoptosis.

The Protective Effects of Ivabradine in Preventing Progression from Viral Myocarditis to Dilated Cardiomyopathy.

To study the beneficial effects of ivabradine in dilated cardiomyopathy (DCM) mice, which evolved from coxsackievirus B3-induced chronic viral myocarditis. Four-to-five-week-old male balb/c mice were inoculated intraperitoneally with coxsackievirus B3 (Strain Nancy) on days 1, 14, and 28. The day of the first virus inoculation was defined as day 1. Thirty-five days later, the surviving chronic viral myocarditis mice were divided randomly into two groups, a treatment group and an untreated group. Ivabradine was administered by gavage for 30 consecutive days in the treatment group, and the untreated group was administered normal saline. Masson's trichrome stain was used to evaluate the fibrosis degree in myocardial tissue. The expression levels of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), collagen I, collagen III and p38-MAPK signaling pathway proteins were detected by Western blot. Electrocardiogram was used to investigate the heart rate and rhythm. The thickness of the ventricular septum and left ventricular posterior wall, left ventricular end diastolic dimension, left ventricular end systolic dimension, left ventricular ejection fractions and fractional shortening were studied by echocardiography. Compared with the untreated chronic viral myocarditis mice, ivabradine significantly increased the survival rate, attenuated the myocardial lesions and fibrosis, improved the impairment of the left ventricular function, diminished the heart dimension, decreased the production of collagen I and collagen III, reduced the expression of the proinflammatory cytokines TNF-α, IL-1ß, and IL-6, and lowered the production of phospho-p38 MAPK. The findings indicate the therapeutic effect of ivabradine in preventing the progression from viral myocarditis to DCM in mice with chronic viral myocarditis induced by coxsackievirus B3, is associated with inhibition of the p38 MAPK pathway, downregulated inflammatory responses and decreased collagen expression. Ivabradine appears a promising approach for the treatment of patients with viral myocarditis.

Expressions of Th1-Th2-Th17 cytokines in mice chronic viral myocarditis / 中国免疫学杂志

Objective:To investigate the expressions of Th 1-Th2-Th17 cytokines in the coxsackievirus B 3-induced mice chronic viral myocarditis(VMC).Methods:BALB/c mice were intraperitoneally(i.p) infected with increased CVB3 for establishing chronic VMC models.Control mice were treated with phosphate-buffered saline(PBS)i.p.Cardiac tissues were obtained 8 weeks after CVB3 in-jection,myocardial histopathologic changes were observed by HE and Masson staining .Th1-Th2-Th17 cytokines in plasma were detected by protein array technology , and their cardiac mRNA expressions were measured by RT-PCR.Results: Compared with the control group,levels of IL-2,IL-5,IL-10,IL-13,IL-17,IL-6,IL-22,IL-21 and TGF-βobviously increased in chronic VMC group (P all<0.05). Conclusion:The imbalance of Th1-Th2-Th17 cytokines may play an important roles in the pathogenesis of chronic VMC .

Protection of Oxymatrine on Myocardium of Mice with Chronic Viral Myocarditis / 实用儿科临床杂志

Objective To observe the expression of anti-cardiac myosin antibody(AMA) and the collagen volume fraction(CVF) in serum in mice with chronic viral myocarditis(CVMC),and to explore the preventive and protective function of oxymatrine on myocardium.Methods BALB/c mice(n=60) were infected with coxsackievirus B3(CVB3) of increased dose biweekly to establish CVMC model.Mice in normal control group(n=8) received equal-volume 9 g?L-1 saline without CVB3 at the same time.The surviving mice in CVMC model group were randomly divided into CVMC control group(n=8) and oxymatrine therapy group(n=8) at the 42th day.From then on,mice in oxymatrine therapy group were treated with oxymatrine at the dose of 100 mg?kg-1?d-1 by gastric perfusion once a day for 28 days,and meanwhile mice in CVMC control group and the normal control group received equal-volume 9 g?L-1 saline by gastric perfusion every day.Then all mice were sacrificed at the end of the experiment.The ratio between heart weight to body weight(HW/BW) was calculated.Myocardium slides were stained with collagen specific Picric acid-Sirius red staining,and the CVF was calculated with image analysis software.The serum level of AMA(optical density value,A value) was detected by enzyme-linked immunosorbent assay(ELISA).Results HW/BW(0.007 9?0.000 3),CVF [(15.30?1.08)%] and the A value of AMA(0.286?0.053) in mice of CVMC control group were increased significantly compared with those in normal control group HW/BW(0.005 5?0.000 2),CVF[(6.84?1.11)%],the A value of AMA(0.160?0.050)(Pa