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Aim To investigate the effeot of Shenqi Fuzheng injection on the prevention of immune myocarditis induced by anti-PD-1 antibody by reducing the production of inflammatory factors and the expression of myocardial injury markers. Methods Thirty-two maie PD-1 humanized mice with C57BL/6 genetic background were randomly divided into control group, myocarditis model group, anti-PD-1 antibody group and Shenqi Fuzheng injection group (n = 8). Except the control group, mice in other groups were intraperitoneally injected with myocardial myosin heavy chain peptide (5 mg • kg
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【Objective】 To explore the effect and mechanism of Fasudil in the treatment of experimental autoimmune myocarditis (EAM) in mice so as to provide a theoretical basis for the clinical use of Fasudil in treating myocarditis. 【Methods】 Balb/c male mice were used as the research objects, and the EAM mice model was constructed using MyHC-α614-629 polypeptide. Mononuclear cells were isolated and cultured to detect the number of mononuclear cells in mouse spleen. Inflammation infiltration, fibrosis and IL-6 expression in mouse myocardial tissue were detected by HE staining, Masson staining and immunohistochemistry, respectively. The protein expressions of Notch1 and IL-6 were detected by Western blotting. qRT-PCR was used to detect the expressions of pro-inflammatory factors (IL-1α, IL-1β and IL-6) as well as key genes of TLRs and NOTCH signaling pathway. 【Results】 EAM mice showed increased HW, decreased BW, increased HW/e-BW, and increased inflammatory infiltration and fibrosis in myocardial tissue. The above-mentioned symptoms or pathological features were improved in EAM mice treated with Fasudil. The analysis showed that the pro-inflammatory factors IL-1α, IL-1β and IL-6 in the myocardial tissue of EAM mice were significantly increased, but only the expression of IL-6 was statistically different after Fasudil treatment compared with the control group. In addition, TLRs signaling pathway might also play an important role in the EAM mice treated with Fasudil. The expressions of IL-6 and Notch1 were consistent, and the expressions of the key genes of NOTCH signaling pathway (Notch1, Hes1 and Jag2) were down-regulated after Fasudil treatment. 【Conclusion】 Fasudil exerts a protective effect on down-regulation of IL-6 expression by inhibiting the NOTCH signaling pathway in EAM mice.
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El término miocarditis hace referencia a una inflamación del miocardio, que puede tener diversas causas (infecciones, tóxicos, enfermedades autoinmunes). Su diagnóstico es desafiante debido al gran espectro de presentaciones clínicas que puede adoptar, muchas veces imitando patologías más prevalentes como el infarto agudo de miocardio. La miocarditis asociada a enfermedades autoinmunes es poco frecuente, y la importancia de reconocerla radica en que el diagnóstico e inicio temprano del tratamiento son cruciales para mejorar su pronóstico. Presentamos aquí un caso clínico de una perimiocarditis lúpica.
Myocarditis refers to an inflammation of the myocardium, which can have various causes (infections, toxic substances, autoimmune diseases). Its diagnosis is challenging due to the wide spectrum of clinical presentations, often mimicking more prevalent pathologies such as acute myocardial infarction. Myocarditis associated with autoimmune diseases is rare, and the importance of recognizing is that early diagnosis and initiation of treatment are crucial to improve its prognosis. We present here a clinical case of lupus perimyocarditis.
O termo miocardite refere-se a uma inflamação do miocárdio, que pode ter várias causas (infecções, substâncias tóxicas, doenças autoimunes). Seu diagnóstico é desafiador devido ao amplo espectro de apresentações clínicas que pode ter, muitas vezes mimetizando patologias mais prevalentes como o infarto agudo do miocárdio. A miocardite associada a doenças autoimunes é rara, e a importância de reconhecê-la reside no fato de que o diagnóstico precoce e o início do tratamento são cruciais para melhorar seu prognóstico. Apresentamos aqui um caso clínico de perimiocardite lúpica.
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Humans , Female , Adult , Heart Failure/therapy , Myocarditis/diagnostic imaging , Chest Pain , Methylprednisolone/therapeutic use , Treatment Outcome , Immunoglobulins, Intravenous/therapeutic use , Cyclophosphamide/therapeutic use , Hydroxychloroquine/therapeutic use , Immunologic Factors/therapeutic use , Immunosuppressive Agents/therapeutic use , Lupus Erythematosus, Systemic/complications , Myocarditis/etiology , Myocarditis/drug therapyABSTRACT
La afectación cardiovascular en pacientes con tirotoxicosis es caracterizada por la presentación de arritmias, fenómenos embólicos, eventos coronarios e insuficiencia cardiaca. Esta última, es una presentación inusual, en la mayoría de las ocasiones acompañada de alto gasto cardiaco, relegando a las de bajo gasto cardiaco a una pequeña proporción de etiología aún por esclarecer. Se presenta el caso de una paciente de sexo femenino con diagnóstico de hipertiroidismo durante la gestación, que un mes poscesárea inició con síntomas de insuficiencia cardiaca en el contexto de tirotoxicosis. Se documentó cardiopatía dilatada con fracción de eyección reducida, cuyos hallazgos por resonancia magnética cardiaca sugirieron el diagnóstico de miocarditis. Se determinó el origen autoinmune secundario a enfermedad de Graves, como etiología de la miocarditis, con adecuada respuesta al manejo inmunosupresor y antitiroideo.
Cardiovascular involvement in patients with thyrotoxicosis is characterized by the presentation of arrhythmias, embolic phenomena, coronary events, and heart failure. The latter is an unusual presentation, in most cases characterized as high-output cardiac failure, relegating the low-output cardiac failure to a small proportion of etiology yet to be clarified. We describe the case of a female patient with diagnosis of hyperthyroidism during pregnancy, who one month after caesarean section began with symptoms of heart failure in the context of thyrotoxicosis. Dilated heart disease with reduced ejection fraction is documented, with findings in the cardiac magnetic resonance that suggested the diagnosis of myocarditis. An autoimmune origin secondary to Graves' disease was determined, as the etiology of the myocarditis, with an adequate response to immunosuppressive and antithyroid management.
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The study is to investigate effects of andrographolide on experimental autoimmune myocarditis (EAM). Lewis rats were immunized on day 0 with porcine cardiac myosin to establish EAM. The EAM rats were treated with either andrographolide (25, 50, 100 mg/kg/day) or vehicle for 21 days. An antigen-specific splenocytes proliferation assay was performed by using the cells from control rats immunized with cardiac myosin. Survival rates, myocardial pathology and myocardial functional parameters (left ventricle end-diastolic pressure, ± dP/dt and left ventricular internal dimension) of EAM rats received andrographolide were significantly improved. Andrographolide treatment caused an decrease in the infiltration of CD3⁺ and CD14⁺ positive cells in myocardial tissue. Moreover, andrographolide treatment caused a reduction in the plasma levels of tumor necrosis factor-alpha, interleukin-17 (IL-17) and myosin-antibody, and an increase in the level of IL-10 in EAM rats. Oral administration of andrographolide resulted in the decreased expression of p-PI3K, p-Akt without any change of PI3K and Akt. Further results indicate andrographolide significantly inhibited myosin-induced proliferation in splenocytes, and this effect was inhibited by co-treatment of SC79 (Akt activator). Our data indicate andrographolide inhibits development of EAM, and this beneficial effect may be due to powerful anti-inflammatory activity and inhibitory effect on PI3K/Akt pathway.
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Animals , Rats , Administration, Oral , Cardiac Myosins , Interleukin-10 , Interleukin-17 , Models, Animal , Myocarditis , Pathology , Plasma , Survival Rate , Tumor Necrosis Factor-alphaABSTRACT
Objective: To explore whether curcumin can improve cardiac function in rats with experimental autoimmune myocarditis (EAM) by enhancing myocardial autophagy activity. Methods: We used 6-week-old Lewis rats to establish a model of autoimmune myocarditis by the classical method of porcine myocardium immunoglobulin. We randomly divided 21 rats into three groups: control group (Con), autoimmune myocarditis group (EAM), and curcumin-treated group (Cur), with 7 in each group. The rats were treated with curcumin for 21 days. The structure and function of rat heart was evaluated by echocardiography on day 22. Western blot was used to detect the expression of microtubule-associated protein light chain 3 (LC3). The expressions of Beclin-1 and ATG-5 in the myocardium were measured by Real-time PCR. Results: The echocardiography showed that left ventricular systolic function was abnormal in EAM rats compared with rats in Con group. After administration of curcumin, rats in Cur group had better left ventricular systolic function than EAM rats. Compared with that in Con group, LC3 expression in EAM group was significantly increased (P=0.026). After curcumin administration, the expression of LC3 increased more obviously than that in EAM group (P=0.014). Beclin-1, an upstream factor of LC3, was significantly increased in EAM group (P=0.041) and increased even higher under administration of curcumin (P=0.003). ATG-5, another LC3 upstream factor, did not significantly differ among the three groups (P=0.108). Conclusion: Curcumin can improve cardiac function in rats with autoimmune myocarditis by inducing myocardial autophagy activity, which is mediated through the promotion of Beclin-1.
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Objective To explore the expression of macrophage migration inhibitory factor(MIF)in rat hearts with experimental autoimmune myocarditis(EAM)and the possible mechanism of resveratrol's therapeutic effect.Methods Experimental myocarditis model was established by using porcine myocardial immunoglobulin. Twenty-four male 6-week-old Lewis rats were randomly divided into control group(Con),EAM model group(MC) and resveratrol treatment group(MC+ Res).All the rats were detected and compared in the cardiac function according to echocardiographic analysis,and the expression of MIF was detected by Western blot.The degree of myocardial injury was detected by HE staining and the degree of macrophage infiltration in the myocardium was detected by immunohistochemistry.Results In control group,there was no significant inflammatory infiltration or myocardial injury in the myocardium.Heavy local infiltration of macrophages,and dissolved and fractured myocardial fibers were observed in model group.Resveratrol significantly decreased macrophage density and myocardial injury in the heart(P＜ 0.05).Compared with those in control group,LVEDs were significantly increased(P＜0.01)while LVEF and LVFS were markedly decreased in model group(P＜0.01).Compared with model group,LVEDs were significantly decreased(P＜0.05)while LVEF and LVFS were markedly increased in resveratrol group(P＜0.05).The protein expression of MIF was markedly increased in rats of model group(P＜0.01),but was decreased in resveratrol group compared with model groups(P＜ 0.05).Conclusion Increased expression of MIF may be involved in the pathogenesis of EAM.The therapeutic effect of resveratrol on EAM may be associated with down-regulated MIF expression and decreased macrophage infiltration.
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Autoimmunity is influenced by genetic,immune,hormonal,and environmental factors.Viral infections may trigger autoimmunity.It has been established that autoimmunity may be a contributing factor in the pathogenesis of heart disease.Myocarditis is defined as inflammation of the heart muscle associated with impaired function of the myocardium.Myocarditis is considered as the most common cause of dilated cardiomyopathy.Myocarditis may be caused by infectious factors and noninfectious factors,noninfectious factors including autoimmune diseases with myocarditis.To gain a better understanding of autoimmune myocarditis,we summarize the pathogenesis and clinical significance of autoimmune myocarditis.
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Objective To explore the effect of CD40 small interfering RNA(siRNA)on the expressions of pe-ripheral blood interleukin(IL)-21 and IL -35 in rats with experimental autoimmune myocarditis (EAM)and its sig-nificance.Methods Twenty 6 -8 week male Lewis rats were divided into normal group,EAMgroup,CD40 siRNA group and siRNA group by using random number table,with 5 rats in each group.The normal rats were induced with phos-phate buffer saline in double foot pads on day 0 and day 7,while the rest 3 groups were induced with cardiac myosin protein to establish EAMmodels.The rats in CD40 siRNA group and siRNA group were respectively injected with CD40 siRNA and siRNA slow virus expression vector through the tail vein of rats on day 7.The rats were executed on 21 day after echocardiogram examination was made.The histopathologic changes were observed by using light microscope and the myocardial histopathology scores were calculated.Enzyme -linked immunosorbent assay was used to determine the levels of IL -21 and IL -35 in peripheral blood.Results (1)Except the normal group,the total incidence rate of rats of each group was 100%,and there was no rat death.(2)Compared with EAM group,the heart mass/body ratio and myocardial histopathology scores were lower in CD40 siRNA group,and the differences were significant (3.13 ±0.21 vs 3.80 ±0.29,2.22 ±0.43 vs 3.32 ±0.51,F =0.332,0.456,all P <0.05).(3)The echocardiogram showed that there was only 1 rat in EAM group with massive pericardial effusion,and there was no pericardial effusion in CD40 siRNA group.EAMgroup,CD40 siRNA group and siRNA group displayed hypertrophy of the ventricular septum and left ventricular wall,narrow heart cavity and weakening of ventricular wall motion.The left ventricular shortening rate in CD40 siRNA group was significantly higher than that in the EAMgroup[(63.34 ±11.06)% vs (38.56 ±6.98)%,F =16.080,P <0.05].(4)The peripheral blood level of IL -21 in CD40 siRNA group was lower than that in EAM group [(141.19 ±17.46)ng/L vs (157.81 ±17.58)ng/L,F =57.008,P <0.05],while its level of IL -35 was signifi-cantly higher than that in the EAMgroup [(195.96 ±18.26)ng/L vs (174.78 ±13.91 )ng/L,F =31.727,P <0.05].(5)The level of IL -21 in peripheral blood was positively correlated with myocardial histopathology scores in EAM group (r = 0.69,P < 0.05 ),but IL -35 was negatively correlated with myocardial histopathology scores (r =-0.64,P <0.05).Conclusions CD40 siRNA might relieve the myocardial inflammation and reduce the myocar-dial injury of EAMrats.The levels of IL -21 and IL -35 can partly reflect the degree of myocardial injury.The mecha-nism may be related to down -regulating the expression IL -21 and up -regulating the expression of IL -35.
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Objective To investigate how gene silence of CD40 by small interfering RNA(siRNA)influences the balance between Th1 / Th2 and Th17 / Treg in rats with experimental autoimmune myocarditis(EAM). Methods Lewis rats were divided into a normal - control group,EAM group,CD40 siRNA - therapy group and siRNA - control group by using random number table. EAM,CD40 siRNA - therapy and siRNA - control groups were immunized on day 0 and day 7 with purified porcine cardiac myosin to establish EAM,and CD40 siRNA was administered intravenously on day 7. The basic data of each group were observed,and the rats were executed on day 21 to study the pathology of myo-cardial tissues and the myocardial histopathology scores were calculated,and than the changes in electrocardiograms (ECG)and echocardiogram were recorded. Enzyme - linked immunosorbent assay(ELISA)was used to determine the levels of interferon(IFN) - γ,interleukin(IL) - 10,IL - 17 and transforming growth factor(TGF)- β in peripheral blood. Results (1)The overall incidence of EAM,CD40 siRNA - therapy and siRNA - control group was 100% ,and no rats died from day 0 to day 21.(2)There were only 2 premature rats in EAM and siRNA - control groups,and the ECGs of normal - control group and CD40 siRNA - therapy group were normal.(3)The echocardiogram of EAM,CD40 siRNA - therapy and siRNA - control group,displayed the left ventricular dilatation,hypertrophy of the left ventricle, the weakening of the left ventricular wall motion,and heart failure,and pericardial effusion was discovered. The left ven-tricular fractional shortening(LVFS)and the left ventricular ejection fraction(LVEF)of rats treated by CD40 siRNA were higher than those of rats in the EAM group[(46. 70 ± 8. 25)% vs(34. 28 ± 11. 81)% ,(80. 92 ± 11. 76)% vs (64. 03 ± 12. 60)% ,F = 0. 652,0. 234,all P ﹤ 0. 05].(4)Pathologic examination of the EAM group,CD40 siRNA therapy group and siRNA control groups,showed myocardial fiber fracture,myocardial tissue necrosis and inflammatory cell infiltration. But myocardial tissue pathological scores of the cardiac tissue of CD40 siRNA therapy group was lower than those of the EAM group(2. 10 ± 1. 07 vs 3. 40 ± 0. 72,F = 1. 290,P ﹤ 0. 05).(5)ELISA method examination re-vealed that the levels of IFN - γ,IL - 4,IL - 17 and TGF - β in EAM group were increased compared with those of nor-mal control group[(1 245. 55 ± 244. 56)ng/ L vs(501. 53 ± 18. 93)ng/ L,(78. 03 ± 10. 47)ng/ L vs(30. 77 ± 1. 74)ng/ L,(80. 82 ± 13. 33)ng/ L vs(27. 98 ± 3. 01)ng/ L,(156. 27 ± 12. 11)ng/ L vs(4. 33 ± 0. 79)ng/ L,t =7. 408,10. 764,9. 250,30. 608,all P ﹤ 0. 05]. However,the levels of IFN - γ and IL - 17 in CD40 siRNA therapy group were lower than those in the EAM group[(940. 62 ± 128. 40)ng/ L vs(1 245. 55 ± 244. 56)ng/ L,(60. 42 ± 12. 40) ng/ L vs(80. 82 ± 13. 33)ng/ L,t = 2. 704,2. 745,all P ﹤ 0. 05],while the levels of IL - 4 and TGF - β were higher [(97. 91 ± 13. 62)ng/ L vs(78. 03 ± 10. 47)ng/ L,(178. 84 ± 12. 10)ng/ L vs(156. 27 ± 12. 11)ng/ L,t = 2. 835, 3. 229,all P ﹤ 0. 05]. Conclusions The administration of CD40 siRNA markedly reduces myocardial inflammation of EAM rats and improves their cardiac function,which can be explained by Th1 - type and Th17 - type cytokines inhibi-ted,Th2 - type and Treg - type cytokines increased,and so then the imbalance of Th1 / Th2 and Th17 / Treg corrected.
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[ ABSTRACT] AIM:To evaluate the effect of intravenous injecting plasmid encoding interleukin-19-IgG on exper-imental autoimmune myocarditis ( EAM) in rats.METHODS:Cardiac myosin was emulsified with equal volume of com-plete Freund’ s adjuvant.The animal model of EAM was established by injecting with the preparation in both footpads of the Lewis rats.The rats were intravenously injected with the plasmid encoding IL-19-IgG on day 6.Echocardiography was per-formed before the rats were sacrificed on day 17.The effect of IL-19-IgG plasmid injection was evaluated by measuring the heart weight/body weight, myocarditis area, relative expression levels of atrial natriuretic peptide ( ANP) and brain natri-uretic peptide (BNP) in the hearts.The mRNA expression levels of related cytokines including IL-18, IL-1β, IL-12p35 and IFN-γwere detected.RESULTS:The rats in model group showed significant myocardial damage and a decrease in the left ventricular functions.The rats in the treatment group injected with IL-19-IgG plasmid showed an improvement of the cardiac functions.The ratio of heart weight/body weight, the area of myocarditis and the mRNA levels of ANP and BNP were significantly lower in IL-19-IgG treatment group than those in model group.The mRNA levels of IL-18, IL-1β, IL-12p35 and IFN-γwere also significantly decreased in IL-19-IgG treatment group.CONCLUSION:Intravenous injection of plasmid encoding IL-19-IgG effectively prevents the development of the left ventricular remodeling and myocardial damage in EAM rats.
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Objective:To observe the expression of B7-H4 in experimental autoimmune myocarditis (EAM).Methods:BALB/c mice were randomly divided into 2 groups:the control group and the experimental group.The mice of experimental group were injected with myosin to establish EAM models , while the mice of control group were injected with complete Freund 's adjuvant and normal saline.All the mice were killed separately at the 14th,21st,30th and 45th day for lymphocyte proliferation assay ,hematoxylin-eosin staining,immunohistochemical staining and real-time PCR.Results:The inflammation infiltration of heart was most serious at the 14th and 21st day,then it was gradually relieved with time;the results of lymphocyte proliferation assay and real-time PCR were similar to that of the inflammation infiltration of heart ,which were in high level at the 14th and 21st day,and they were both higher than that of the control group ( P<0.05 );B7-H4 protein were only detected in the experimental group ,and it was constantly expressed during the whole experiment on the endothelium of heart with myocarditis.Conclusion:B7-H4 participates in the progress of EAM ,and it may be a new way of studying the mechanism of myocarditis.
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Objective To investigate the effect of CD40siRNA on the pathologic changes and T helper lymphocyte (Th)-17 cells of myocardium and IL-17,IL-23 of serum in rats with experimental autoimmune myocarditis (EAM).Methods Forty 6-8 week old healthy male Lewis rats with body weight of 185-210 g were divided into EAM group,CD40siRNA group,siRNA group,and normal control group randomly,with 10 rats in each group.The rats in EAM group,CD40siRNA group and siRNA group were induced by immunization with cardiac C protein and completed Freund adjuvant in double foot pads.The rats in normal control group were injected with PBS buffer in double foot pads.On the 8th day after immunization,the rats in CD40siRNA group were injected with CD40 siRNA expression vector,and the rats in siRNA group were injected with siRNA expression vector.The rats were sacrificed on day 21 after inoculation.The histopathologic changes were observed by light microscope and the myocardial histopathology scores were calculated.The expression of RORC mRNA of myocardium was detected by real-time quantitative polymerase chain reaction (RTPCR).Enzyme linked immunoabsorption assay was used to determine the serum level of IL-17 and IL-23.Results Compared with EAM group,the myocardial histopathology score(2.34 ±0.60 vs 3.40 ±0.35,P ＜0.05),the expression ofRORC mRNA(2.13 ±0.28 vs 2.93 ±0.36,P ＜0.05) and the serum level of IL-17 (114.38 ± 8.29 vs 148.70 ± 5.04,P ＜ 0.05) and IL-23 (107.00 ± 7.69 vs 136.98 ± 23.16,P ＜ 0.05) were significantly lower in CD40 siRNA group.Conclusions It is suggested that CD40 siRNA expression vector might reduce myocardial injury by inhibiting Th-17 activation and down-regulating the expression of IL-17 and IL-23.
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To better understand the role of macrophages in early stages of experimental autoimmune myocarditis (EAM), we compared the expression of inducible nitric oxide synthase (iNOS) and arginase-1, markers for classically activated M1 and alternatively activated M2 macrophages, respectively, in the hearts of EAM-affected and control rats. Immunohistochemical evidence revealed that both iNOS-positive and arginase 1-positive macrophages were found in EAM lesions, while some cells were co-localized with both markers. This finding suggests that the increased level of arginase-1, which is partly from M2 macrophages, contributes to the modulation of EAM, possibly through the reduction of nitric oxide in the lesion.
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Animals , Rats , Arginase , Heart , Macrophages , Myocarditis , Nitric Oxide , Nitric Oxide Synthase Type IIABSTRACT
ObjectiveTo assess the efficacy of herpes virus entry mediator (HVEM) gene modifled dendritic cells (DCs) in protecting against myosin induced myocarditis,and to investigate the involving mechanism.MethodsWe treated experimental autoimmune myocarditis (EAM) mice with myosin-pulsed DCs which were transfected with HVEM-expressing adenovirus (Ad-HVEM) or control vectors,then evaluated myocarditis,plasm cTn [ and autoantibody by histopathology,fluoroimmunoassay,and ELISA,respectively.ResultsWe found that DCs transfected with Ad-HVEM (DC-Ad-HVEM) could protect against EAM.Further study showed DC-Ad-HVEM could produce regulatory cytokine IL-10,and IL-10 promoted the production of a key regulatory T cell subset which is important in peripheral tolerance.The T cells mediated protection against EAM.ConclusionThis study suggest that myosin-DC-Ad-HVEM cell gene therapy is a safe and effective way for inhibiting the development of EAM,and the signal net mediated by HVEM plays different roles in different cells.
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Objective:To study adenovirus mediated transfer of TGF ?1 in treatment of mice autoimmune myocarditis. Methods: Experimental autoimmune myocarditis was induced in BALB/c mice using purified myosin from porcine heart. TGF ?1 was transferred into mice by intravenous injection of adenovirus encoding TGF ?1. Plasma level of myosin autoantibody was detected by indirect ELISA method and plasma level of troponin I was assayed using fluorescence immune assay method. The protective effects of TGF ?1 were evaluated from 3 aspects: (1) the degree of infiltrative inflammatory cells in the heart; (2) the plasma level of myosin autoantibody; (3) the plasma level of troponin I. Results: TGF ?1 successfully ameliorated the myocarditis. Plasma level of troponin I and myosin autoantibody decreased significantly( P