scholarly journals Transplantation of Fibroblast Sheets with Blood Mononuclear Cell Culture Exerts Cardioprotective Effects by Enhancing Anti-Inflammation and Vasculogenic Potential in Rat Experimental Autoimmune Myocarditis Model

Biology ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 106
Author(s):  
Kaori Sekine ◽  
Akira T. Kawaguchi ◽  
Masaki Miyazawa ◽  
Haruo Hanawa ◽  
Shinichi Matsuda ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Mononuclear Cells ◽  
Therapeutic Option ◽  
Cell Sheet ◽  
Left Ventricular ◽  
Fulminant Myocarditis ◽  
Autoimmune Myocarditis ◽  
Experimental Autoimmune Myocarditis ◽  
Anti Inflammatory ◽  
Experimental Autoimmune

Fulminant myocarditis causes impaired cardiac function, leading to poor prognosis and heart failure. Cell sheet engineering is an effective therapeutic option for improving cardiac function. Naïve blood mononuclear cells (MNCs) have been previously shown to enhance the quality and quantity of cellular fractions (QQMNCs) with anti-inflammatory and vasculogenic potential using the one culture system. Herein, we investigated whether autologous cell sheet transplant with QQMNCs improves cardiac function in a rat model with experimental autoimmune myocarditis (EAM). Fibroblast sheets (F-sheet), prepared from EAM rats, were co-cultured with or without QQMNCs (QQ+F sheet) on temperature-responsive dishes. QQ+F sheet induced higher expression of anti-inflammatory and vasculogenic genes (Vegf-b, Hgf, Il-10, and Mrc1/Cd206) than the F sheet. EAM rats were transplanted with either QQ+F sheet or F-sheet, and the left ventricular (LV) hemodynamic analysis was performed using cardiac catheterization. Among the three groups (QQ+F sheet, F-sheet, operation control), the QQ+F sheet transplant group showed alleviation of end-diastolic pressure–volume relationship on a volume load to the same level as that in the healthy group. Histological analysis revealed that QQ+F sheet transplantation promoted revascularization and mitigated fibrosis by limiting LV remodeling. Therefore, autologous QQMNC-modified F-sheets may be a beneficial therapeutic option for EAM.

Abstract 5261: Platelet-Depletion Ameliorates Cardiac Function and Disease Severity in Experimental Autoimmune Myocarditis

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Martin Russ ◽  
Barbara Seliger ◽  
Steffen Hauptmann ◽  
Rene Marty ◽  
Jürgen Bukur ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cardiac Function ◽  
Left Ventricular ◽  
Inflammatory Cardiomyopathy ◽  
Autoimmune Myocarditis ◽  
Severity Scores ◽  
Experimental Autoimmune Myocarditis ◽  
Platelet Depletion ◽  
Experimental Autoimmune

Introduction: Experimental Autoimmune Myocarditis (EAM) is a CD4+ T cell mediated model of inflammatory cardiomyopathy. Activated platelets express CD154, a molecule critical to adaptive immune responses, which has been implicated in platelet-mediated modulation of inflammation. Hypothesis: Platelets are critical for the generation of heart-specific, autoreactive T-cell responses in a model of experimental Autoimmune Myocarditis. Methods: BALB/c mice were immunized twice at day 0 and day 7 with 100μg alpha-MyHC-peptide (614–29) together with Complete Freund‘s adjuvant. Platelets were markedly depleted by i.v. injection of a GP1alpha antibody every 5th day (n=8). Control mice were injected with a non-depleting isotype antibody (n=8). Mice were assessed at day 28 for heart dimensions and cardiac function using echocardiography. After lethal anesthesia, hearts were removed and analyzed for heart weight/body weight ratio and histological severity scores. CD4+ T-cells were isolated from spleens, and analyzed for CD154 and IL-17 expression using FACS after in vitro re-stimulation on alpha-MyHC pulsed, irradiated antigen presenting cells. Results: Modest platelet depletion protected from left ventricular dilatation, and preserved left ventricular ejection fraction in immunized mice. Myocarditis prevalence and severity scores were significantly reduced in depleted animals. Relative numbers of spleen-derived CD4+ T-cells expressing CD154 or IL-17, were significantly reduced in the treatment group (table ). Conclusion: Our findings suggest that platelets might play a critical role in the development of heart-specific autoimmunity and cardiomyopathy. Further studies are needed to confirm these findings, which suggest a novel treatment approach for inflammatory cardiomyopathy. Echocardiography - Histology - FACS

scholarly journals Sex-Specific Differences of the Inflammatory State in Experimental Autoimmune Myocarditis

2021 ◽  
Vol 12 ◽  
Author(s):  
Maria Luisa Barcena ◽  
Sarah Jeuthe ◽  
Maximilian H. Niehues ◽  
Sofya Pozdniakova ◽  
Natalie Haritonow ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Female Rats ◽  
Male Rats ◽  
Inflammatory Factors ◽  
Autoimmune Myocarditis ◽  
Male And Female Rats ◽  
Inflammatory Phenotype ◽  
Experimental Autoimmune Myocarditis ◽  
Anti Inflammatory ◽  
Experimental Autoimmune

Increasing evidence suggests male sex as a potential risk factor for a higher incidence of cardiac fibrosis, stronger cardiac inflammation, and dilated cardiomyopathy (DCM) in human myocarditis. Chronic activation of the immune response in myocarditis may trigger autoimmunity. The experimental autoimmune myocarditis (EAM) model has been well established for the study of autoimmune myocarditis, however the role of sex in this pathology has not been fully explored. In this study, we investigated sex differences in the inflammatory response in the EAM model. We analyzed the cardiac function, as well as the inflammatory stage and fibrosis formation in the heart of EAM male and female rats. 21 days after induction of EAM, male EAM rats showed a decreased ejection fraction, stroke volume and cardiac output, while females did not. A significantly elevated number of infiltrates was detected in myocardium in both sexes, indicating the activation of macrophages following EAM induction. The level of anti-inflammatory macrophages (CD68+ ArgI+) was only significantly increased in female hearts. The expression of Col3A1 and fibrosis formation were more prominent in males. Furthermore, prominent pro-inflammatory factors were increased only in male rats. These findings indicate sex-specific alterations in the inflammatory stage of EAM, with a pro-inflammatory phenotype appearing in males and an anti-inflammatory phenotype in females, which both significantly affect cardiac function in autoimmune myocarditis.

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.

P3688Familial recurrent autoimmune myocarditis associated with a truncating nonsense mutation of the desmoplakin gene

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
W Poller ◽  
S Klaassen ◽  
J Haas ◽  
Z Kaya ◽  
H.-C Mochmann ◽  
...  
Keyword(s):  
Family History ◽  
Protein Level ◽  
Mononuclear Cells ◽  
Troponin I ◽  
Immune Cell ◽  
Mutation Screening ◽  
Left Ventricular ◽  
Fulminant Myocarditis ◽  
Autoimmune Myocarditis ◽  
Truncating Mutation

Abstract Background Arrhythmogenic cardiomyopathy (AC) is an important cause of ventricular arrhythmias in children and young adults. AC is associated with mutation of desmosomal proteins, however, cardiac disease penetrance is incomplete and the clinical course varies widely without recognizable exogenous or epi/genetic co-factors. Importantly, DSP mutation carriers may also display entirely non-cardiac e.g. dermatological phenotypes. Methods and results In two brothers with recurrent fulminant myocarditis, mutation screening of 218 cardiomyopathy-related genes identified a truncating mutation Arg1458* of desmoplakin (DSP). DSP immunhistology unexpectedly revealed complete loss (“knockout”) of DSP protein in endomyocardial biopsies (EMBs), but none of the histological anomalies of AC. Criteria for histological diagnosis of myocarditis were not either fulfilled, and cardiac MRI revealed no features associated with AC. Screening for infections was negative, there was no substance abuse, medication or vaccination. Possible disease triggers were competitive sport events. Myosin and troponin I autoantibodies were detected at titers up to 1:320. We used allele-specific RT-PCR to distinguish if the patients' allele classified as “normal” was actually defective due to promotor mutation or epigenetic silencing. RT-PCRs were done on EMBs and peripheral blood mononuclear cells (PBMCs). In a cohort of dilated cardiomyopathy (DCM) patients we were able to detect DSP transcripts in both, PBMC and left-ventricular heart tissue. RNA sequencing of human PBMC subpopulations suggested that DSP transcription may be restricted to certain immune cell subtypes. RT-PCRs revealed that both Arg1458* carriers have a functional second DSP allele, indicating that their “DSP knockout” occurs at the protein level and may be due to protein instability and degradation within desmosomes. We screened additional existing cohorts for such variants and identified stopgain variant Gln307Ter in a 37-yrs-old woman with ARVC. This patient's sister died from heart failure at the age of 39. In a 59-yrs-old female LVNC patient, stopgain variant Y1391X was identified. Here, family history was unclear, her brother probably died from coronary artery disease. In a 71-yrs-old female DCM patient with no family history, stopgain variant Tyr1512Ter was identified. Conclusions The described patients with DSP truncations strongly suggest the existence of additional genetic or exogenous modifiers driving pathogenesis either way. DSP defects may cause recurrent myocarditis, and mutation screening is advisable to enable early detection of high-risk patients with similar phenotypes. Our finding of complete myocardial DSP protein loss emphasizes that DNA sequencing may miss critical molecular disturbances. It is indispensable to also analyze transcriptome and protein level in the tissue actually affected in a patient in order to recognize his/her individual pathogenesis.

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