scholarly journals Effects of 1, 25-Dihydroxyvitamin D3 on Experimental Autoimmune Myocarditis in Mice

2016 ◽  
Vol 38 (6) ◽  
pp. 2219-2229 ◽  
Author(s):  
Fen Hu ◽  
Lianhua Yan ◽  
Shuai Lu ◽  
Wenhan Ma ◽  
Ya Wang ◽  
...  
Keyword(s):  
Beclin 1 ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Heart Weight ◽  
Autoimmune Myocarditis ◽  
Inflammatory Infiltration ◽  
Western Blots ◽  
Dihydroxyvitamin D3 ◽  
Multiple Systems ◽  
Experimental Autoimmune Myocarditis ◽  
Experimental Autoimmune

Background/Aims: Myocarditis is an important inflammatory disease of the heart which causes life-threatening conditions. 1, 25(OH)2 D3 has effects on multiple systems and diseases. The present study was aimed to investigate the effect of 1, 25(OH)2 D3 on experimental autoimmune myocarditis (EAM), and explored the underlying mechanisms involved. Methods: EAM was induced by immunizing BALB/c mice with cardiac α-myosin heavy chain peptides (MyHC-α). 1, 25(OH)2 D3 (1,000 ng/kg once) or vehicle was administered intraperitoneally every other day during the entire experiment. On day 21, transthoracic echocardiography was performed and cardiac inflammatory infiltration was detected by hematoxylin and eosin (HE). The terminal deoxynucleotidyl transferase mediated dUTP nick-end labeling (TUNEL) assay, and Western blots for the expression of protein caspase-3 and cleaved-caspase3 were used to evaluate apoptosis. Transmission electron microscopy and Western blots for the expression of protein Beclin-1, LC3B, and P62 were used to evaluate autophagy. Results: The ratio of heart weight/body weight was significantly reduced in 1, 25(OH)2 D3 -treated EAM mice, compared with vehicle -treated ones. 1, 25(OH)2 D3 treatment improved cardiac function, diminished cell infiltration in cardiac, suppressed myocardial apoptosis, decreased the number of autophagosomes, and decreased the protein expression of Beclin-1, LC3-II and p62. Conclusions: The present results demonstrated that administration of 1, 25(OH)2 D3 decreased EAM severity. 1, 25(OH)2 D3 treatment may be a feasible therapeutic approach for EAM.

scholarly journals Programmed Death-Ligand 2 Deficiency Exacerbates Experimental Autoimmune Myocarditis in Mice

2021 ◽  
Vol 22 (3) ◽  
pp. 1426
Author(s):  
Siqi Li ◽  
Kazuko Tajiri ◽  
Nobuyuki Murakoshi ◽  
DongZhu Xu ◽  
Saori Yonebayashi ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Receptor ◽  
Cd4 T Cell ◽  
Myocardial Inflammation ◽  
Autoimmune Myocarditis ◽  
Inflammatory Infiltration ◽  
Programmed Death ◽  
Experimental Autoimmune Myocarditis ◽  
Deficient Mice ◽  
Experimental Autoimmune

Programmed death ligand 2 (PD-L2) is the second ligand of programmed death 1 (PD-1) protein. In autoimmune myocarditis, the protective roles of PD-1 and its first ligand programmed death ligand 1 (PD-L1) have been well documented; however, the role of PD-L2 remains unknown. In this study, we report that PD-L2 deficiency exacerbates myocardial inflammation in mice with experimental autoimmune myocarditis (EAM). EAM was established in wild-type (WT) and PD-L2-deficient mice by immunization with murine cardiac myosin peptide. We found that PD-L2-deficient mice had more serious inflammatory infiltration in the heart and a significantly higher myocarditis severity score than WT mice. PD-L2-deficient dendritic cells (DCs) enhanced CD4+ T cell proliferation in the presence of T cell receptor and CD28 signaling. These data suggest that PD-L2 on DCs protects against autoreactive CD4+ T cell expansion and severe inflammation in mice with EAM.

scholarly journals Activated myofibroblasts promote cardiac hypertrophy and systolic dysfunction independently of cardiac fibrosis in experimental autoimmune myocarditis

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
K Tkacz ◽  
A Jazwa-Kusior ◽  
F Rolski ◽  
E Dzialo ◽  
K Weglarczyk ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Dilated Cardiomyopathy ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Systolic Dysfunction ◽  
Heart Weight ◽  
Type I ◽  
Autoimmune Myocarditis ◽  
Experimental Autoimmune Myocarditis ◽  
Experimental Autoimmune

Abstract Background/Introduction Heart-specific inflammation – myocarditis is a common cause dilated cardiomyopathy which is characterized by pathological tissue remodeling, ventricular stiffening, cardiomyopathy and heart failure. In experimental autoimmune myocarditis (EAM) susceptible mice immunized with alpha myosin heavy chain (αMyHC) and complete Freund's adjuvant (CFA) develop acute myocarditis driven by autoreactive CD4+ T cells that is followed by progressive fibrosis, cardiomyopathy and systolic dysfunction. Purpose The aim of the study was to investigate the role of cardiac fibroblasts and myofibroblasts in myocarditis and post-inflammatory dilated cardiomyopathy in mouse model of EAM. Methods EAM was induced in BALB/c mice by immunization with αMyHC/CFA. We used reporter mice expressing EGFP under collagen type I promoter (Coll-EGFP) and RFP under a control of α-smooth muscle actin (αSMA) promoter (αSMA-RFP) and transgenic αSMA-TK mice with ganciclovir-inducible ablation of proliferating myofibroblasts. Cardiac cells were quantified using flow cytometry. Cardiac fibroblasts (CD45-CD31-EGFP+) were sorted from healthy and myocarditis-positive (day 21) mice using BD FACSAria™ II Cell Sorter and analyzed for the whole genome transcriptomics by RNA sequencing. Echocardiography was performed on Vevo 2100 Imaging System. Cardiac fibrosis was assessed by Trichrome Massons's staining and hydroxyproline assay, whereas cardiac hypertrophy by analysing cross-sectional cardiomyocyte area. Profibrotic gene expression was assessed by qRT-PCR. Results The total number of cardiac fibroblasts (CD45-CD31-EGFP+) and the subset of myofibroblasts (CD45-CD31-EGFP+RFP+) remained unchanged at inflammatory (d21) and fibrotic stages (d40). Analysis of differentially expressed genes (min. 2x fold change, p value <0.05) pointed out activation of immune processes (mainly chemokine production), response to stress, cytoskeletal and extracellular matrix re-organization in cardiac fibroblasts in response to myocarditis. αSMA-TK mice treated with ganciclovir (from day 21) showed comparable percent of fibrotic area, but significantly reduced heart weight, decreased cardiomyocyte hypertrophy and improved ejection fraction and cardiac output at day 40 comparing to PBS-treated mice. Ganciclovir-treated mice showed also attenuated cardiac Acta2 and Srf but markedly enhanced Mmp2 expression. Conclusions In EAM model cardiac fibroblasts actively participate in proinflammatory and profibrotic responses, while activated myofibroblasts contribute to dilated cardiomyopathy development independently of cardiac fibrosis. FUNDunding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Science Centre (Poland)

scholarly journals Blocking LFA-1 Aggravates Cardiac Inflammation in Experimental Autoimmune Myocarditis

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1267 ◽  
Author(s):  
Ludwig T. Weckbach ◽  
Andreas Uhl ◽  
Felicitas Boehm ◽  
Valentina Seitelberger ◽  
Bruno C. Huber ◽  
...  
Keyword(s):  
Body Weight ◽  
Weight Ratio ◽  
Heart Weight ◽  
Lymphocyte Function ◽  
Body Weight Ratio ◽  
Antibody Treatment ◽  
Autoimmune Myocarditis ◽  
Cardiac Inflammation ◽  
Experimental Autoimmune Myocarditis ◽  
Experimental Autoimmune

The lymphocyte function-associated antigen 1 (LFA-1) is a member of the beta2-integrin family and plays a pivotal role for T cell activation and leukocyte trafficking under inflammatory conditions. Blocking LFA-1 has reduced or aggravated inflammation depending on the inflammation model. To investigate the effect of LFA-1 in myocarditis, mice with experimental autoimmune myocarditis (EAM) were treated with a function blocking anti-LFA-1 antibody from day 1 of disease until day 21, the peak of inflammation. Cardiac inflammation was evaluated by measuring infiltration of leukocytes into the inflamed cardiac tissue using histology and flow cytometry and was assessed by analysis of the heart weight/body weight ratio. LFA-1 antibody treatment severely enhanced leukocyte infiltration, in particular infiltration of CD11b+ monocytes, F4/80+ macrophages, CD4+ T cells, Ly6G+ neutrophils, and CD133+ progenitor cells at peak of inflammation which was accompanied by an increased heart weight/body weight ratio. Thus, blocking LFA-1 starting at the time of immunization severely aggravated acute cardiac inflammation in the EAM model.

scholarly journals RIP1/RIP3/MLKL Mediates Myocardial Function Through Necroptosis in Experimental Autoimmune Myocarditis

2021 ◽  
Vol 8 ◽  
Author(s):  
Yujing Wu ◽  
Zhenzhong Zheng ◽  
Xiantong Cao ◽  
Qing Yang ◽  
Vikram Norton ◽  
...  
Keyword(s):  
Cell Death ◽  
Myocardial Function ◽  
Viral Myocarditis ◽  
Cardiac Myosin ◽  
Autoimmune Myocarditis ◽  
Potential Therapeutic Target ◽  
Inflammatory Infiltration ◽  
Experimental Autoimmune Myocarditis ◽  
Experimental Autoimmune

Cardiomyopathy often leads to dilated cardiomyopathy (DCM) when caused by viral myocarditis. Apoptosis is long considered as the principal process of cell death in cardiomyocytes, but programmed necrosis or necroptosis is recently believed to play an important role in cardiomyocyte cell death. We investigated the role of necroptosis and its interdependency with other processes of cell death, autophagy, and apoptosis in a rat system of experimental autoimmune myocarditis (EAM). We successfully created a rat model system of EAM by injecting porcine cardiac myosin (PCM) and showed that in EAM, all three forms of cell death increase considerably, resulting in the deterioration of cardiac conditions with an increase in inflammatory infiltration in cardiomyocytes. To explore whether necroptosis occurs in EAM rats independent of autophagy, we treated EAM rats with a RIP1/RIP3/MLKL kinase-mediated necroptosis inhibitor, Necrostatin-1 (Nec-1). In Nec-1 treated rats, cell death proceeds through apoptosis but has no significant effect on autophagy. In contrast, autophagy inhibitor 3-Methyl Adenine (3-MA) increases necroptosis, implying that blockage of autophagy must be compensated through necroptosis. Caspase 8 inhibitor zVAD-fmk blocks apoptosis but increases both necroptosis and autophagy. However, all necroptosis, apoptosis, and autophagy inhibitors independently reduce inflammatory infiltration in cardiomyocytes and improve cardiac conditions. Since apoptosis or autophagy is involved in many important cellular aspects, instead of suppressing these two major cell death processes, Nec1 can be developed as a potential therapeutic target for inflammatory myocarditis.

Abstract 17425: Curcumin Ameliorates Experimental Autoimmune Myocarditis by Inducing M2 Macrophage Polarization

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Shanshan Gao ◽  
Na Liu ◽  
Lijun Wang ◽  
Fangyuan Chen ◽  
Hongjun You ◽  
...  
Keyword(s):  
Mrna Level ◽  
Heart Weight ◽  
M2 Macrophage ◽  
Autoimmune Myocarditis ◽  
Ppar Γ ◽  
Raw264.7 Macrophages ◽  
M2 Polarization ◽  
Experimental Autoimmune Myocarditis ◽  
M2 Phenotype ◽  
Experimental Autoimmune

AIMS: Our previous study showed that curcumin, the main active ingredient in turmeric, induces the polarization of macrophages to anti-inflammatory M2 phenotype. In this study, we addressed the underlying mechanisms and observed whether curcumin exerts its protective effects on experimental autoimmune myocarditis (EAM) by facilitating the M2 phenotype polarization of macrophages. METHODS AND RESULTS: The mRNA and protein expression of M2 markers, including MMR, Arg-1, KLF-4 and PPAR-γ, were obviously up-regulated in curcumin-treated RAW264.7 macrophages. Curcumin increased not only IL-4 and IL-13 mRNA expression, but also protein content of these two cytokines in supernatant. The STAT6 inhibitor leflunomide antagonized the induction of MMR, Arg-1, KLF-4 and PPAR-γ by curcumin in RAW264.7 cells, which is suggested that curcumin induces macrophages M2 polarization through secretion of IL-4 and IL-13 in an autocrine manner. In vivo, 6-week-old male Lewis rats were immunized with myosin to induce EAM and orally administrated with curcumin (50mg/kg/day) or corn oil for 3 weeks after myosin injection. Cardiac functional parameters, including LVFS, EF, LVESD and HR, were significantly improved by curcumin treatment. Curcumin also reduced the heart weight-to-body weight ratio, inflammatory cell infiltration and the myocardial mRNA level of IL-1β and iNOS. Meanwhile, the myocardial mRNA level of KLF4, MMR and Arg-1 were markedly up-regulated by curcumin. Immunofluorescence assay showed that the number of CD68+MMR+ and CD68+Arg-1+ double positive macrophages in curcumin-treated myocardial tissue was obviously more than vehicle-treated ones. CONCLUSIONS: Taken together, these results show that curcumin ameliorates EAM by attenuating inflammation and by inducing macrophage M2 polarization.

scholarly journals Quercetin Ameliorates Experimental Autoimmune Myocarditis in Rats

2010 ◽  
Vol 13 (3) ◽  
pp. 311 ◽  
Author(s):  
Marina Milenković ◽  
Nevena Arsenović-Ranin ◽  
Zorica Stojić-Vukanić ◽  
Biljana Bufan ◽  
Dragana Vučićević ◽  
...  
Keyword(s):  
Histopathological Examination ◽  
Weight Ratio ◽  
Heart Weight ◽  
Tnf Alpha ◽  
Dark Agouti ◽  
Autoimmune Myocarditis ◽  
Experimental Autoimmune Myocarditis ◽  
Anti Inflammatory ◽  
Culture Supernatants ◽  
Experimental Autoimmune

Purpose: Experimental autoimmune myocarditis (EAM) in rats is an animal model of human giant cell myocarditis and post-myocarditis dilated cardiomyopathy. The pathogenesis of EAM has not been elucidated, but there is accumulating evidence that cytokines secreted from monocytes/macrophages and T cells play a crucial role in the induction and progression of disease. Flavonoids are a large group of polyphenolic compounds abundantly present in the human diet, which scavenge oxygen radicals and have anti-inflammatory activities. Having in mind in vivo beneficial effects of flavonoid quercetin in different animal models of immunoinflammatory diseases such as experimental autoimmune encephalomyelitis and adjuvant arthritis, on the one side, and its in vitro suppressive effect on production of tumor necrosis factor–alpha (TNF-alpha on the other side, we investigated the effects of quercetin on EAM in rats. Methods: Myocarditis was induced in Dark Agouti (DA) rats by injection of porcine cardiac myosin and quercetin at doses of 10 or 20 mg/kg was orally administered from days 0 to 21 after induction of disease. The severity of myocarditis was evaluated by determination of heart weight / body weight ratio (Hw/Bw) and histopathological examination of hearts. The levels of cytokines (TNF-alpha, IL-12, IL-17 and IL-10) in serum and lymph node cells (LNC) culture supernatants were measured by ELISA. Results: The rats treated with 20 mg/kg of quercetin had significantly decreased incidence of EAM, Hw/Bw, macroscopic and microscopic scores of hearts. Further, in EAM rats treated with quercetin levels of TNF-alpha and IL-17 were significantly lower, while the level of IL-10 was significantly higher both in serum and culture supernatants of LNC stimulated with concanavalin A compared with vehicle-treated animals. Conclusions: The present study suggests that quercetin ameliorates EAM, at least in part, by interfering production of proinflammatory (TNF-alpha and IL-17) and/or anti-inflammatory (IL-10) cytokines.

scholarly journals STAT4 silencing underlies a novel inhibitory role of microRNA-141-3p in inflammation response of mice with experimental autoimmune myocarditis

2019 ◽  
Vol 317 (3) ◽  
pp. H531-H540 ◽  
Author(s):  
Aiqun Pan ◽  
Yuying Tan ◽  
Zhihao Wang ◽  
Guoliang Xu
Keyword(s):  
Body Weight ◽  
Cardiac Function ◽  
Weight Ratio ◽  
Heart Weight ◽  
Inflammatory Factor ◽  
Body Weight Ratio ◽  
Autoimmune Myocarditis ◽  
Experimental Autoimmune Myocarditis ◽  
Experimental Autoimmune

As an inflammatory disease afflicting the heart muscle, autoimmune myocarditis (AM) represents one of the foremost causes of heart failure. Accumulating evidence has implicated microRNAs (miRNAs) in the process of inflammation and autoimmunity. Hence, the current study aimed to investigate the mechanism by which miR-141-3p influences experimental AM (EAM). An EAM mouse model was established using 6-wk old male BALB/c mice, after which the expression of miR-141-3p and STAT4 was measured. Gain-of-function and loss-of-function investigations were performed to identify the functional role of miR-141-3p and STAT4 in EAM. Heart weight-to-body weight ratio, cardiac function, and degree of inflammation, as well as the levels of inflammation factors (IFN-γ, TNF-α, IL-2, IL-6, and IL-17) in the serum were detected. STAT4 was subsequently verified to be upregulated, and miR-141-3p was downregulated in the EAM mice. Furthermore, the overexpression of miR-141-3p or silencing of STAT4 was observed to reduce the heart weight-to-body weight ratio of EAM mice and improve cardiac function, while alleviating the degree of inflammatory cell infiltration in the myocardial tissue. Meanwhile, the overexpression of miR-141-3p was identified to diminish serum inflammatory factor levels by downregulating STAT4. Additionally, miR-141-3p could bind to STAT4 to downregulate its expression, ultimately mitigating inflammation and inducing an anti-inflammatory effect in EAM mice. Taken together, upregulation of miR-141-3p alleviates the inflammatory response in EAM mice by inhibiting STAT4, providing a promising intervention target for the molecular treatment of AM. NEW & NOTEWORTHY miR-141-3p is poorly expressed, and STAT4 is upregulated in experimental autoimmune myocarditis (EAM) mice. Overexpressing miR-141-3p inhibits EAM. miR-141-3p binds to and suppresses STAT4 expression. miR-141-3p overexpression inhibits inflammatory factors by downregulating STAT4. This study provides new insights into the treatment of autoimmune myocarditis.

Inhibition of NF-κB activation by a novel IKK inhibitor reduces the severity of experimental autoimmune myocarditis via suppression of T-cell activation

2013 ◽  
Vol 305 (12) ◽  
pp. H1761-H1771 ◽  
Author(s):  
Ryo Watanabe ◽  
Ryoko Wakizono Azuma ◽  
Jun-ichi Suzuki ◽  
Masahito Ogawa ◽  
Akiko Itai ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Weight Ratio ◽  
Heart Weight ◽  
Autoimmune Myocarditis ◽  
Inflammatory Reactions ◽  
Experimental Autoimmune Myocarditis ◽  
Experimental Autoimmune

NF-κB, which is activated by the inhibitor of NF-κB kinase (IKK), is involved in the progression of inflammatory disease. However, the effect of IKK inhibition on the progression of myocarditis is unknown. We examined the effect of IKK inhibition on the progression of myocarditis. Lewis rats were immunized with porcine cardiac myosin to induce experimental autoimmune myocarditis (EAM). We administered the IKK inhibitor (IMD-0354; 15 mg·kg−1·day−1) or vehicle to EAM rats daily. Hearts were harvested 21 days after immunization. Although the untreated EAM group showed increased heart weight-to-body weight ratio, and severe myocardial damage, these changes were attenuated in the IKK inhibitor-treated group. Moreover, IKK inhibitor administration significantly reduced NF-κB activation and mRNA expression of IFN-γ, IL-2, and monocyte chemoattractant protein-1 in myocardium compared with vehicle administration. In vitro study showed that the IKK inhibitor treatment inhibited T-cell proliferation and Th1 cytokines production induced by myosin stimulation. The IKK inhibitor ameliorated EAM by suppressing inflammatory reactions via suppression of T-cell activation.

scholarly journals IL-17 Upregulates MCP-1 Expression via Act1 / TRAF6 / TAK1 in Experimental Autoimmune Myocarditis

2021 ◽  
Author(s):  
xiao huang ◽  
Zhuolun Li ◽  
Xinhe Shen ◽  
na nie ◽  
yan shen
Keyword(s):  
Myocardial Tissue ◽  
Inflammatory Factor ◽  
Mononuclear Cell Infiltration ◽  
Autoimmune Myocarditis ◽  
Inflammatory Infiltration ◽  
Mrna And Protein Expression ◽  
Experimental Autoimmune Myocarditis ◽  
Experimental Autoimmune ◽  
Important Cytokine

Abstract Myocarditis is a myocardial inflammatory infiltration heterogeneous disease. At present, various interventions are not effective in the treatment of myocarditis. IL-17, an important pro‐inflammatory factor secreted mainly by Th17 cells, can promote the expression of multiple cytokines. MCP-1 is an important cytokine that mediates mononuclear cell infiltration. Studies have found that IL-17 could stimulate the expression of MCP-1 to mediate inflammatory infiltration. But the mechanism by which IL-17 induces MCP-1 expression in experimental autoimmune myocarditis (EAM) remains unclear. The purpose of this study is to establish an EAM model to explore the role of Act1/TRAF6/TAK1 cascade in the induction of MCP-1 by IL-17. In the present study, we found that in EAM, IL-17 could stimulate the expression of MCP-1 by activating Act1/TRAF6/TAK1 cascade. After interfering TAK1 with si-TAK1, myocardial tissue inflammation was greatly alleviated, and both MCP-1 mRNA and protein expression were downregulated. In conclusion, IL-17 can activate AP-1, NF-κB via Act1/TRAF6/TAK1 upregulation of MCP-1 expression in EAM.

Sign in / Sign up

Export Citation Format

Share Document