47 results on '"Kapka Miteva"'
Search Results
2. Sex- and age-related differences in the inflammatory properties of cardiac fibroblasts: impact on the cardiosplenic axis and cardiac fibrosis
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Kathleen Pappritz, Sarah-Lena Puhl, Isabel Matz, Erik Brauer, Yi Xuan Shia, Muhammad El-Shafeey, Suzanne E. Koch, Kapka Miteva, Christin Mucha, Georg N. Duda, Ansgar Petersen, Sabine Steffens, Carsten Tschöpe, and Sophie Van Linthout
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aging ,sex ,cardiac fibroblasts ,cardiosplenic axis ,monocytes ,fibrosis ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
BackgroundAge and sex are prominent risk factors for heart failure and determinants of structural and functional changes of the heart. Cardiac fibroblasts (cFB) are beyond their task as extracellular matrix-producing cells further recognized as inflammation-supporting cells. The present study aimed to evaluate the impact of sex and age on the inflammatory potential of cFB and its impact on the cardiosplenic axis and cardiac fibrosis.MaterialsLeft ventricles (LV) of 3- and 12-months old male and female C57BL/6J mice were harvested for immunohistochemistry, immunofluorescence and cFB outgrowth culture and the spleen for flow cytometry. LV-derived cFB and respective supernatants were characterized.ResultsLV-derived cFB from 3-months old male mice exhibited a higher inflammatory capacity, as indicated by a higher gene expression of CC-chemokine ligand (CCL) 2, and CCL7 compared to cFB derived from 3-months old female mice. The resulting higher CCL2/chemokine C-X3-C motif ligand (Cx3CL1) and CCL7/Cx3CL1 protein ratio in cell culture supernatants of 3-months old male vs. female cFB was reflected by a higher migration of Ly6Chigh monocytes towards supernatant from 3-months old male vs. female cFB. In vivo a lower ratio of splenic pro-inflammatory Ly6Chigh to anti-inflammatory Ly6Clow monocytes was found in 3-months old male vs. female mice, suggesting a higher attraction of Ly6Chigh compared to Ly6Clow monocytes towards the heart in male vs. female mice. In agreement, the percentage of pro-inflammatory CD68+ CD206− macrophages was higher in the LV of male vs. female mice at this age, whereas the percentage of anti-inflammatory CD68+ CD206+ macrophages was higher in the LV of 3-months old female mice compared to age-matched male animals. In parallel, the percentage of splenic TGF-β+ cells was higher in both 3- and 12-months old female vs. male mice, as further reflected by the higher pro-fibrotic potential of female vs. male splenocytes at both ages. In addition, female mice displayed a higher total LV collagen content compared to age-matched male mice, whereby collagen content of female cFB was higher compared to male cFB at the age of 12-months.ConclusionAge- and sex-dependent differences in cardiac fibrosis and inflammation are related to age- and sex-dependent variations in the inflammatory properties of cardiac fibroblasts.
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- 2023
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3. Epitope of antiphospholipid antibodies retrieved from peptide microarray based on R39‐R43 of β2‐glycoprotein I
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Marc Moghbel, Aline Roth, Daniela Baptista, Kapka Miteva, Fabienne Burger, Fabrizio Montecucco, Nicolas Vuilleumier, François Mach, and Karim J. Brandt
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β2GP1 ,antibody ,antiphospholipid syndrome ,ApoH ,autoimmune disease ,ELISA ,Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Abstract Background Antiphospholipid antibody (aPL) syndrome (APS) is an autoimmune disease characterized by the presence of antiphospholipid antibodies and thromboembolic or pregnancy complications. Although cryptic epitope R39‐R43 belonging to beta‐2‐glycoprotein 1 (β2GP1) has been identified as the main antigenic determinant for aPLs, we have recently demonstrated that the epitope is a motif determined by the polarity, rather than by the sequence or charge of amino acids. Objective In the present study, we wanted to identify the association of residues needed to obtain the highest aPL affinity. Methods Based on the epitope R39‐R43 and our identified motif, we generated a printed peptide microarray of 676 different peptides. These peptides have been then screened for their ability to interact with the plasmas from 11 well‐characterized APS patients and confirmed by surface plasma resonance assay. Results and Conclusions We identified a peptide that selectively bound immunoglobulin G (IgG) derived from APS patients with 100 times more affinity than β2GP1, Domain I, or epitope R39‐R43. This peptide is able to inhibit the activity of IgG derived from APS patients in vitro. We have also generated a monoclonal IgG antibody against this peptide. Using both peptide and monoclonal antibody, we have been able to develop a fully standardized indirect colorimetric immunoassay with highly sensitivity. The identification of the optimized peptide offers a new standardized and accurate tool for diagnostics of APS. Furthermore, having increased affinity for aPL, this peptide could represent a useful tool as prevention strategy for APS and an alternative to the use of anticoagulants.
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- 2022
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4. Impact of Syndecan-2-Selected Mesenchymal Stromal Cells on the Early Onset of Diabetic Cardiomyopathy in Diabetic db/db Mice
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Kathleen Pappritz, Fengquan Dong, Kapka Miteva, Arpad Kovacs, Muhammad El-Shafeey, Bahtiyar Kerim, Lisa O'Flynn, Stephen Joseph Elliman, Timothy O'Brien, Nazha Hamdani, Carsten Tschöpe, and Sophie Van Linthout
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type 2 diabetes ,diabetic cardiomyopathy ,syndecan-2/CD362+-selected stromal cells ,immunomodulation ,cardiomyocyte stiffness ,cardiac fibrosis ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
Background: Mesenchymal stromal cells (MSCs) are an attractive cell type for cell therapy given their immunomodulatory, anti-fibrotic, and endothelial-protective features. The heparin sulfate proteoglycan, syndecan-2/CD362, has been identified as a functional marker for MSC isolation, allowing one to obtain a homogeneous cell product that meets regulatory requirements for clinical use. We previously assessed the impact of wild-type (WT), CD362−, and CD362+ MSCs on local changes in protein distribution in left ventricular (LV) tissue and on LV function in an experimental model of early-onset diabetic cardiomyopathy. The present study aimed to further explore their impact on mechanisms underlying diastolic dysfunction in this model.Materials: For this purpose, 1 × 106 WT, CD362−, or CD362+ MSCs were intravenously (i.v.) injected into 20-week-old diabetic BKS.Cg-m+/+Leprdb/BomTac, i.e., db/db mice. Control animals (db+/db) were injected with the equivalent volume of phosphate-buffered saline (PBS) alone. After 4 weeks, mice were sacrificed for further analysis.Results: Treatment with all three MSC populations had no impact on blood glucose levels in db/db mice. WT, CD362−, and CD362+ MSC application restored LV nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) levels in db/db mice, which correlated with a reduction in cardiomyocyte stiffness. Furthermore, all stromal cells were able to increase arteriole density in db/db mice. The effect of CD362+ MSCs on NO and cGMP levels, cardiomyocyte stiffness, and arteriole density was less pronounced than in mice treated with WT or CD362− MSCs. Analysis of collagen I and III protein expression revealed that fibrosis had not yet developed at this stage of experimental diabetic cardiomyopathy. All MSCs reduced the number of cardiac CD3+ and CD68+ cells in db/db mice, whereas only splenocytes from CD362−- and CD362+-db/db mice exhibited a lower pro-fibrotic potential compared to splenocytes from db/db mice.Conclusion: CD362+ MSC application decreased cardiomyocyte stiffness, increased myocardial NO and cGMP levels, and increased arteriole density, although to a lesser extent than WT and CD362− MSCs in an experimental model of early-onset diabetic cardiomyopathy without cardiac fibrosis. These findings suggest that the degree in improvement of cardiomyocyte stiffness following CD362+ MSC application was insufficient to improve diastolic function.
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- 2021
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5. The E3 Ubiquitin Ligase Peli1 Deficiency Promotes Atherosclerosis Progression
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Fabienne Burger, Daniela Baptista, Aline Roth, Karim J. Brandt, and Kapka Miteva
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atherosclerosis ,foam cells ,VSMCs ,plaque stability ,ubiquitin ligase ,Cytology ,QH573-671 - Abstract
Background: Atherosclerosis is a chronic inflammatory vascular disease and the main cause of death and morbidity. Emerging evidence suggests that ubiquitination plays an important role in the pathogenesis of atherosclerosis including control of vascular inflammation, vascular smooth muscle cell (VSMC) function and atherosclerotic plaque stability. Peli1 a type of E3 ubiquitin ligase has emerged as a critical regulator of innate and adaptive immunity, however, its role in atherosclerosis remains to be elucidated. Methods: Apoe−/− mice and Peli1-deficient Apoe−/− Peli1−/− mice were subject to high cholesterol diet. Post sacrifice, serum was collected, and atherosclerotic plaque size and parameters of atherosclerotic plaque stability were evaluated. Immunoprofiling and foam cell quantification were performed. Results: Peli1 deficiency does not affect atherosclerosis lesion burden and cholesterol levels, but promotes VSMCs foam cells formation, necrotic core expansion, collagen, and fibrous cap reduction. Apoe−/− Peli1−/− mice exhibit a storm of inflammatory cytokines, expansion of Th1, Th1, Th17, and Tfh cells, a decrease in regulatory T and B cells and induction of pro-atherogenic serum level of IgG2a and IgE. Conclusions: In the present study, we uncover a crucial role for Peli1 in atherosclerosis as an important regulator of inflammation and VSMCs phenotypic modulation and subsequently atherosclerotic plaque destabilization.
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- 2022
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6. Single-Cell Analysis Uncovers Osteoblast Factor Growth Differentiation Factor 10 as Mediator of Vascular Smooth Muscle Cell Phenotypic Modulation Associated with Plaque Rupture in Human Carotid Artery Disease
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Karim J. Brandt, Fabienne Burger, Daniela Baptista, Aline Roth, Rafaela Fernandes da Silva, Fabrizio Montecucco, Francois Mach, and Kapka Miteva
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vascular smooth muscle cells ,atherosclerosis ,carotid artery disease ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
(1) Background: Vascular smooth muscle cells (VSMCs) undergo a complex phenotypic switch in response to atherosclerosis environmental triggers, contributing to atherosclerosis disease progression. However, the complex heterogeneity of VSMCs and how VSMC dedifferentiation affects human carotid artery disease (CAD) risk has not been clearly established. (2) Method: A single-cell RNA sequencing analysis of CD45− cells derived from the atherosclerotic aorta of Apolipoprotein E-deficient (Apoe−/−) mice on a normal cholesterol diet (NCD) or a high cholesterol diet (HCD), respecting the site-specific predisposition to atherosclerosis was performed. Growth Differentiation Factor 10 (GDF10) role in VSMCs phenotypic switch was investigated via flow cytometry, immunofluorescence in human atherosclerotic plaques. (3) Results: scRNAseq analysis revealed the transcriptomic profile of seven clusters, five of which showed disease-relevant gene signature of VSMC macrophagic calcific phenotype, VSMC mesenchymal chondrogenic phenotype, VSMC inflammatory and fibro-phenotype and VSMC inflammatory phenotype. Osteoblast factor GDF10 involved in ossification and osteoblast differentiation emerged as a hallmark of VSMCs undergoing phenotypic switch. Under hypercholesteremia, GDF10 triggered VSMC osteogenic switch in vitro. The abundance of GDF10 expressing osteogenic-like VSMCs cells was linked to the occurrence of carotid artery disease (CAD) events. (4) Conclusions: Taken together, these results provide evidence about GDF10-mediated VSMC osteogenic switch, with a likely detrimental role in atherosclerotic plaque stability.
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- 2022
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7. Single-Cell RNA-Seq Reveals a Crosstalk between Hyaluronan Receptor LYVE-1-Expressing Macrophages and Vascular Smooth Muscle Cells
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Fabienne Burger, Daniela Baptista, Aline Roth, Karim J. Brandt, Rafaela Fernandes da Silva, Fabrizio Montecucco, François Mach, and Kapka Miteva
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resident-like macrophages ,LYVE-1 ,CCL24 ,VSMC transdifferentiation ,osteogenic-like cells ,vascular calcification ,Cytology ,QH573-671 - Abstract
Background: Atherosclerosis is a chronic inflammatory disease where macrophages participate in the progression of the disease. However, the role of resident-like macrophages (res-like) in the atherosclerotic aorta is not completely understood. Methods: A single-cell RNA sequencing analysis of CD45+ leukocytes in the atherosclerotic aorta of apolipoprotein E–deficient (Apoe−/−) mice on a normal cholesterol diet (NCD) or a high cholesterol diet (HCD), respecting the side-to-specific predisposition to atherosclerosis, was performed. A population of res-like macrophages expressing hyaluronan receptor LYVE-1 was investigated via flow cytometry, co-culture experiments, and immunofluorescence in human atherosclerotic plaques from carotid artery disease patients (CAD). Results: We identified 12 principal leukocyte clusters with distinct atherosclerosis disease-relevant gene expression signatures. LYVE-1+ res-like macrophages, expressing a high level of CC motif chemokine ligand 24 (CCL24, eotaxin-2), expanded under hypercholesteremia in Apoe−/− mice and promoted VSMC phenotypic modulation to osteoblast/chondrocyte-like cells, ex vivo, in a CCL24-dependent manner. Moreover, the abundance of LYVE-1+CCL24+ macrophages and elevated systemic levels of CCL24 were associated with vascular calcification and CAD events. Conclusions: LYVE-1 res-like macrophages, via the secretion of CCL24, promote the transdifferentiation of VSMC to osteogenic-like cells with a possible role in vascular calcification and likely a detrimental role in atherosclerotic plaque destabilization.
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- 2022
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8. Mesenchymal stromal cells inhibit NLRP3 inflammasome activation in a model of Coxsackievirus B3-induced inflammatory cardiomyopathy
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Kapka Miteva, Kathleen Pappritz, Marzena Sosnowski, Muhammad El-Shafeey, Irene Müller, Fengquan Dong, Konstantinos Savvatis, Jochen Ringe, Carsten Tschöpe, and Sophie Van Linthout
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Medicine ,Science - Abstract
Abstract Inflammation in myocarditis induces cardiac injury and triggers disease progression to heart failure. NLRP3 inflammasome activation is a newly identified amplifying step in the pathogenesis of myocarditis. We previously have demonstrated that mesenchymal stromal cells (MSC) are cardioprotective in Coxsackievirus B3 (CVB3)-induced myocarditis. In this study, MSC markedly inhibited left ventricular (LV) NOD2, NLRP3, ASC, caspase-1, IL-1β, and IL-18 mRNA expression in CVB3-infected mice. ASC protein expression, essential for NLRP3 inflammasome assembly, increased upon CVB3 infection and was abrogated in MSC-treated mice. Concomitantly, CVB3 infection in vitro induced NOD2 expression, NLRP3 inflammasome activation and IL-1β secretion in HL-1 cells, which was abolished after MSC supplementation. The inhibitory effect of MSC on NLRP3 inflammasome activity in HL-1 cells was partly mediated via secretion of the anti-oxidative protein stanniocalcin-1. Furthermore, MSC application in CVB3-infected mice reduced the percentage of NOD2-, ASC-, p10- and/or IL-1β-positive splenic macrophages, natural killer cells, and dendritic cells. The suppressive effect of MSC on inflammasome activation was associated with normalized expression of prominent regulators of myocardial contractility and fibrosis to levels comparable to control mice. In conclusion, MSC treatment in myocarditis could be a promising strategy limiting the adverse consequences of cardiac and systemic NLRP3 inflammasome activation.
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- 2018
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9. NLRP3 Inflammasome Activation Controls Vascular Smooth Muscle Cells Phenotypic Switch in Atherosclerosis
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Fabienne Burger, Daniela Baptista, Aline Roth, Rafaela Fernandes da Silva, Fabrizio Montecucco, François Mach, Karim J. Brandt, and Kapka Miteva
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NLRP3 inflammasome activation ,vascular smooth muscle ,vascular smooth muscle phenotypic switch ,atherosclerosis ,atherosclerosis plaques stability ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
(1) Background: Monocytes and nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome orchestrate lipid-driven amplification of vascular inflammation promoting the disruption of the fibrous cap. The components of the NLRP3 inflammasome are expressed in macrophages and foam cells within human carotid atherosclerotic plaques and VSMCs in hypertension. Whether monocytes and NLRP3 inflammasome activation are direct triggers of VSMC phenotypic switch and plaque disruption need to be investigated. (2) Methods: The direct effect of oxLDL-activated monocytes in VSMCs co-cultured system was demonstrated via flow cytometry, qPCR, ELISA, caspase 1, and pyroptosis assay. Aortic roots of VSMCs lineage tracing mice fed normal or high cholesterol diet and human atherosclerotic plaques were used for immunofluorescence quantification of NLRP3 inflammasome activation/VSMCs phenotypic switch. (3) Results: OxLDL-activated monocytes reduced α-SMA, SM22α, Oct-4, and upregulation of KLF-4 and macrophage markers MAC2, F4/80 and CD68 expression as well as caspase 1 activation, IL-1β secretion, and pyroptosis in VSMCs. Increased caspase 1 and IL-1β in phenotypically modified VSMCs was detected in the aortic roots of VSMCs lineage tracing mice fed high cholesterol diet and in human atherosclerotic plaques from carotid artery disease patients who experienced a stroke. (4) Conclusions: Taken together, these results provide evidence that monocyte promote VSMC phenotypic switch through VSMC NLRP3 inflammasome activation with a likely detrimental role in atherosclerotic plaque stability in human atherosclerosis.
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- 2021
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10. Anti-Apolipoprotein A-1 IgG Influences Neutrophil Extracellular Trap Content at Distinct Regions of Human Carotid Plaques
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Rafaela F. da Silva, Daniela Baptista, Aline Roth, Kapka Miteva, Fabienne Burger, Nicolas Vuilleumier, Federico Carbone, Fabrizio Montecucco, François Mach, and Karim J. Brandt
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atherosclerosis ,vulnerable plaques ,anti-apoA-1 IgG ,neutrophil extracellular traps ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Background: Neutrophils accumulate in atherosclerotic plaques. Neutrophil extracellular traps (NET) were recently identified in experimental atherosclerosis and in complex human lesions. However, not much is known about the NET marker citrullinated histone-3 (H3Cit) expression and functionality in human carotid plaques. Moreover, the association between the proatherosclerotic autoantibody anti-apolipoprotein A-1 (anti-ApoA-1 IgG) and NET has never been investigated. Methods: Atherosclerotic plaques have been obtained from 36 patients with severe carotid stenosis that underwent carotid endarterectomy for severe carotid stenosis. Samples were sectioned into upstream and downstream regions from the same artery segment. Plaque composition and expression of NET markers neutrophil elastase (NE) and H3Cit were quantified by immunohistochemistry. H3Cit expression and function was evaluated by immunofluorescence and confocal analysis in a subset of patients. Results: Pathological features of vulnerable phenotypes were exacerbated in plaques developed at downstream regions, including higher accumulation of neutrophils and enhanced expression of NE and H3Cit, as compared to plaques from upstream regions. The H3Cit signal was also more intense in downstream regions, with significant extracellular distribution in spaces outside of neutrophils. The percentage of H3Cit colocalization with CD66b (neutrophils) was markedly lower in downstream portions of carotid plaques, confirming the extrusion of NET in this region. In agreement, the maximum distance of the H3Cit signal from neutrophils, extrapolated from vortex distance calculation in all possible directions, was also higher in downstream plaques. The serum anti-ApoA-1index positively correlated with the expression of H3Cit in downstream segments of plaques. Expression of the H3Cit signal outside of neutrophils and H3Cit maximal distance from CD66b-positive cells increased in plaques from serum positive anti-ApoA-1 patients compared with serum negative patients. Conclusion: NET elements are differentially expressed in upstream versus downstream regions of human carotid plaques and may be influenced by circulating levels of anti-ApoA-1 IgG. These findings could warrant the investigation of NET elements as potential markers of vulnerability.
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- 2020
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11. Cardiac Migration of Endogenous Mesenchymal Stromal Cells in Patients with Inflammatory Cardiomyopathy
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Caroline Schmidt-Lucke, Felicitas Escher, Sophie Van Linthout, Uwe Kühl, Kapka Miteva, Jochen Ringe, Thomas Zobel, Heinz-Peter Schultheiss, and Carsten Tschöpe
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Pathology ,RB1-214 - Abstract
Introduction. Mesenchymal stromal cells (MSC) have immunomodulatory features. The aim of this study was to investigate the migration and homing potential of endogenous circulating MSC in virus negative inflammatory cardiomyopathy (CMi). Methods. In 29 patients with n=23 or without n=6 CMi undergoing endomyocardial biopsies (EMB), transcardiac gradients (TCGs) of circulating MSC were measured by flow cytometry from blood simultaneously sampled from aorta and coronary sinus. The presence of MSC in EMB, cardiac inflammation, and SDF-1α mRNA expression were detected via immunohistochemistry and real-time PCR. Results. MSC defined as CD45−CD34−CD11b−CD73+CD90+ cells accounted for 0.010 [0.0025–0.048]%/peripheral mononuclear cell (PMNC) and as CD45−CD34−CD11b−CD73+CD105+ cells for 0.019 [0.0026–0.067]%/PMNC, both with similar counts in patients with or without cardiac inflammation. There was a 29.9% P
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- 2015
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12. Immunomodulatory Effects of Mesenchymal Stromal Cells Revisited in the Context of Inflammatory Cardiomyopathy
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Kapka Miteva, Sophie Van Linthout, Hans-Dieter Volk, and Carsten Tschöpe
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Internal medicine ,RC31-1245 - Abstract
Myocarditis is a common inflammatory cardiomyopathy, associated with cardiomyocyte apoptosis, which can lead to chronic left ventricular dysfunction. Under conventional heart failure therapy, inflammatory cardiomyopathy typically has a progressive course, indicating a need for alternative therapeutic strategies to improve long-term outcomes. Experimental and clinical studies consistently support the application of cellular transplantation as a strategy to improve myocardial function. Mesenchymal stromal cells (MSCs) mediate distinct paracrine effects supporting endogenous regeneration, but most important are their remarkable immunoregulatory properties. In this review, an overview of current knowledge on immunopathology in myocarditis will be given. Furthermore, current research regarding the immunomodulatory properties of MSCs in the context of myocarditis will be discussed. Finally, the impact of MSC priming by the environment on their functionality and the advantages of systemic administration of MSCs under myocarditis are outlined.
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- 2013
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13. Mesenchymal stromal cells but not cardiac fibroblasts exert beneficial systemic immunomodulatory effects in experimental myocarditis.
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Konstantinos Savvatis, Sophie van Linthout, Kapka Miteva, Kathleen Pappritz, Dirk Westermann, Joerg C Schefold, Gerhard Fusch, Alice Weithäuser, Ursula Rauch, Peter-Moritz Becher, Karin Klingel, Jochen Ringe, Andreas Kurtz, Heinz-Peter Schultheiss, and Carsten Tschöpe
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Medicine ,Science - Abstract
Systemic application of mesenchymal stromal cells (MSCs) in inflammatory cardiomyopathy exerts cardiobeneficial effects. The mode of action is unclear since a sufficient and long-acting cardiac homing of MSCs is unlikely. We therefore investigated the regulation of the immune response in coxsackievirus B3 (CVB3)-induced acute myocarditis after intravenous application of MSCs. Wildtype mice were infected with CVB3 and treated with either PBS, human MSCs or human cardiac fibroblasts intravenously 1 day after infection. Seven days after infection, MSCs could be detected in the spleen, heart, pancreas, liver, lung and kidney, whereby the highest presence was observed in the lung. MSCs increased significantly the myocardial expression of HGF and decreased the expression of the proinflammatory cytokines TNFα, IL1β and IL6 as well as the severity of myocarditis and ameliorated the left ventricular dysfunction measured by conductance catheter. MSCs upregulated the production of IFNγ in CD4+ and CD8+ cells, the number of IL10-producing regulatory T cells and the apoptosis rate of T cells in the spleen. An increased number of CD4+CD25+FoxP3 could be found in the spleen as well as in the circulation. In contrast, application of human cardiac fibroblasts had no effect on the severity of myocarditis and the systemic immune response observed after MSCs-administration. In conclusion, modulation of the immune response in extracardiac organs is associated with cardiobeneficial effects in experimental inflammatory cardiomyopathy after systemic application of MSCs.
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- 2012
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14. Human cardiac-derived adherent proliferating cells reduce murine acute Coxsackievirus B3-induced myocarditis.
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Kapka Miteva, Marion Haag, Jun Peng, Kostas Savvatis, Peter Moritz Becher, Martina Seifert, Katrin Warstat, Dirk Westermann, Jochen Ringe, Michael Sittinger, Heinz-Peter Schultheiss, Carsten Tschöpe, and Sophie Van Linthout
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Medicine ,Science - Abstract
BACKGROUND: Under conventional heart failure therapy, inflammatory cardiomyopathy typically has a progressive course, indicating a need for alternative therapeutic strategies to improve long-term outcomes. We recently isolated and identified novel cardiac-derived cells from human cardiac biopsies: cardiac-derived adherent proliferating cells (CAPs). They have similarities with mesenchymal stromal cells, which are known for their anti-apoptotic and immunomodulatory properties. We explored whether CAPs application could be a novel strategy to improve acute Coxsackievirus B3 (CVB3)-induced myocarditis. METHODOLOGY/PRINCIPAL FINDINGS: To evaluate the safety of our approach, we first analyzed the expression of the coxsackie- and adenovirus receptor (CAR) and the co-receptor CD55 on CAPs, which are both required for effective CVB3 infectivity. We could demonstrate that CAPs only minimally express both receptors, which translates to minimal CVB3 copy numbers, and without viral particle release after CVB3 infection. Co-culture of CAPs with CVB3-infected HL-1 cardiomyocytes resulted in a reduction of CVB3-induced HL-1 apoptosis and viral progeny release. In addition, CAPs reduced CD4 and CD8 T cell proliferation. All CAPs-mediated protective effects were nitric oxide- and interleukin-10-dependent and required interferon-γ. In an acute murine model of CVB3-induced myocarditis, application of CAPs led to a decrease of cardiac apoptosis, cardiac CVB3 viral load and improved left ventricular contractility parameters. This was associated with a decline in cardiac mononuclear cell activity, an increase in T regulatory cells and T cell apoptosis, and an increase in left ventricular interleukin-10 and interferon-γ mRNA expression. CONCLUSIONS: We conclude that CAPs are a unique type of cardiac-derived cells and promising tools to improve acute CVB3-induced myocarditis.
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- 2011
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15. Follicular regulatory helper T cells control the response of regulatory B cells to a high-cholesterol diet
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Daniela Baptista, Kapka Miteva, Fabienne Burger, Nikolaos Stergiopulos, Karim J. Brandt, Rodrigo A. Fraga-Silva, Catherine Martel, Aline Roth, and François Mach
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Cholesterol diet ,Adoptive cell transfer ,Mice, Knockout, ApoE ,Physiology ,Follicular helper T cell (TFH) ,Cell ,030204 cardiovascular system & hematology ,Cholesterol, Dietary ,0302 clinical medicine ,Follicular phase ,AcademicSubjects/MED00200 ,Lymphangiogenesis ,Aorta ,Cells, Cultured ,ddc:616 ,B-Lymphocytes, Regulatory ,0303 health sciences ,education.field_of_study ,musculoskeletal, neural, and ocular physiology ,follicular helper cell (t-fh) ,Cell Differentiation ,Adoptive Transfer ,Plaque, Atherosclerotic ,3. Good health ,Cell biology ,lymphangiogenesis ,Phenotype ,medicine.anatomical_structure ,Cardiology and Cardiovascular Medicine ,Helper t-cells ,medicine.medical_specialty ,T Follicular Helper Cells ,T cell ,Regulatory B cells ,Population ,Aortic Diseases ,macromolecular substances ,Biology ,Diet, High-Fat ,regulatory b cell ,03 medical and health sciences ,Immune system ,Internal medicine ,Physiology (medical) ,medicine ,Animals ,Atherosclerosis and Lipid Biology ,education ,B cell ,030304 developmental biology ,Follicular regulatory helper T cells (TFR) ,follicular regulatory helper t cells (t-fr) ,Regulatory B cell ,Original Articles ,Atherosclerosis ,Mice, Inbred C57BL ,Disease Models, Animal ,Endocrinology ,nervous system ,atherosclerosis - Abstract
Aims B cell functions in the process of atherogenesis have been investigated but several aspects remain to be clarified., Methods and results In this study, we show that follicular regulatory helper T cells (T-FR) control regulatory B cell (B-REG) populations in Apoe(-/)(-) mice models on a high-cholesterol diet (HCD). Feeding mice with HCD resulted in up-regulation of T-FR and B-REG cell populations, causing the suppression of proatherogenic follicular helper T cell (T-FH) response. T-FH cell modulation is correlated with the growth of atherosclerotic plaque size in thoracoabdominal aortas and aortic root plaques, suggesting that T-FR cells are atheroprotective. During adoptive transfer experiments, T-FR cells transferred into HCD mice decreased T-FH cell populations, atherosclerotic plaque size, while B-REG cell population and lymphangiogenesis are significantly increased., Conclusion Our results demonstrate that, through different strategies, both T-FR and T-FH cells modulate anti- and proatherosclerotic immune processes in an Apoe(-/-) mice model since T-FR cells are able to regulate both T-FH and B-REG cell populations as well as lymphangiogenesis and lipoprotein metabolism., [GRAPHICS]
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- 2020
16. Combined Genetic Deletion of IL (Interleukin)-4, IL-5, IL-9, and IL-13 Does Not Affect Ischemic Brain Injury in Mice
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Stefano Fumagalli, Maria Grazia De Simoni, Carlo Perego, Kapka Miteva, and Marinos Kallikourdis
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Pathology ,medicine.medical_specialty ,Ischemia ,Neuroprotection ,Brain ischemia ,Lesion ,03 medical and health sciences ,0302 clinical medicine ,medicine.artery ,Medicine ,030304 developmental biology ,Advanced and Specialized Nursing ,0303 health sciences ,Glial fibrillary acidic protein ,biology ,Microglia ,business.industry ,Interleukin ,medicine.disease ,medicine.anatomical_structure ,Middle cerebral artery ,biology.protein ,Neurology (clinical) ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business ,030217 neurology & neurosurgery - Abstract
Background and Purpose— After ischemic injury, microglia and infiltrated macrophages may acquire different polarization phenotypes promoting inflammation and injury (M1) or repair and protection (M2). There is evidence that immunomodulation, via type 2 helper T-cells (Th2) cytokines, exerts neuroprotection after ischemia. We investigated the consequences of simultaneous genetic deletion of Th2 cytokines (IL [interleukin]-4, IL-5, IL-9, IL-13) on the histopathologic outcome, microglia and infiltrated macrophages markers, and ischemic microenvironment at different time points after ischemic injury in mice subjected to permanent occlusion of the middle cerebral artery. Methods— Wild-type and Th2 cytokine-deficient mice (4KO) were subjected to permanent occlusion of the middle cerebral artery by electrocoagulation and followed up to 5 weeks after permanent occlusion of the middle cerebral artery. Neuropathologic outcome was assessed at 24 hours (n=6), 7 days (n=6), and 5 weeks (n=6–7) by examination of the ischemic lesion, neuronal count, microglia and infiltrated macrophages markers, brain atrophy, collagen deposition, and GFAP (glial fibrillary acidic protein) immunohistochemistry. Selected gene expression was investigated at 7 days (n=6). Results— 4KO mice showed no difference in lesion and neuronal count 7 days and up to 5 weeks after permanent occlusion of the middle cerebral artery compared with wild type. Ischemic 4KO mice had lower CD16/32 expression at 24 hours, lower CD11b and CD16/32 expression at 7 days than wild type. They had higher CD206 expression at 24 hours, higher CD206 and arginase1 at 7 days, and increased mRNA for CXCL9 (chemokine [C-X-C motif] ligand 9) compared with wild type. Additional histopathologic analysis, including brain atrophy, gliotic scar, and collagenous scar confirmed no difference between genotypes at 5 weeks. Conclusions— This study casts light on the proposed neuroprotective function of Th2 cytokines, showing that combined IL-4, IL-5, IL-9, IL-13 deletion does not affect the neuropathologic response to ischemic stroke in the subacute and chronic phases. Our findings indicate that Th2 cytokines are not an essential neuroimmunological cue able to drive the brain’s ischemic outcome.
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- 2019
17. Atherosclerotic plaque vulnerability is increased in mouse model of lupus
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François Mach, Fabienne Burger, Kapka Miteva, Aline Roth, Sabrina Pagano, Fabrizio Montecucco, Nicolas Vuilleumier, Daniela Baptista, Federico Carbone, Karim J. Brandt, and Marie-Laure Santiago-Raber
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0301 basic medicine ,Pathology ,medicine.medical_specialty ,lcsh:Medicine ,Enzyme-Linked Immunosorbent Assay ,Spleen ,ddc:616.07 ,030204 cardiovascular system & hematology ,Real-Time Polymerase Chain Reaction ,Article ,Muscle hypertrophy ,Lesion ,Mice ,03 medical and health sciences ,Systemic lupus erythematosus ,0302 clinical medicine ,medicine ,Animals ,Lupus Erythematosus, Systemic ,lcsh:Science ,Autoantibodies ,ddc:616 ,Mice, Knockout ,Kidney ,Multidisciplinary ,Lupus erythematosus ,business.industry ,lcsh:R ,Autoantibody ,Sinus of Valsalva ,Atherosclerosis ,medicine.disease ,Plaque, Atherosclerotic ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,lipids (amino acids, peptides, and proteins) ,lcsh:Q ,Disease Susceptibility ,Lymph ,medicine.symptom ,business - Abstract
Anti-apolipoprotein A-1 (anti-apoA-1 IgG) and anti-double stranded DNA (anti-dsDNA IgG) autoantibodies have been described as mediators of atherogenesis in mice and humans. In the present study, we aim to investigate the association between atherosclerotic parameters, autoantibodies and plaque vulnerability in the context of systemic lupus erythematosus (SLE). We therefore bred a lupus prone-mouse model (Nba2.Yaa mice) with Apoe−/− mice resulting in Apoe−/−Nba2.Yaa mice spontaneously producing anti-apoA-1 IgG antibodies. Although Apoe−/−Nba2.Yaa and Apoe−/− mice subject to a high cholesterol diet displayed similar atherosclerosis lesions size in aortic roots and abdominal aorta, the levels of macrophage and neutrophil infiltration, collagen, MMP-8 and MMP-9 and pro-MMP-9 expression in Apoe−/−Nba2.Yaa mice indicated features of atherosclerotic plaque vulnerability. Even though Apoe−/−Nba2.Yaa mice and Apoe−/− mice had similar lipid levels, Apoe−/−Nba2.Yaa mice showed higher anti-apoA-1 and anti-dsDNA IgG levels. Apoe−/−Nba2.Yaa mice displayed a reduction of the size of the kidney, splenomegaly and lymph nodes (LN) hypertrophy. In addition, anti-apoA-1 and anti-dsDNA IgG increased also in relation with mRNA levels of GATA3, IL-4, Bcl-6 and CD20 in the spleen and aortic arch of Apoe−/−Nba2.Yaa mice. Our data show that although atherosclerosis-lupus-prone Apoe−/−Nba2.Yaa mice did not exhibit exacerbated atherosclerotic lesion size, they did show features of atherosclerotic plaque destabilization in correlation with the increase of pro-atherogenic autoantibodies.
- Published
- 2020
18. Anti-Apolipoprotein A-1 IgG Influences Neutrophil Extracellular Trap Content at Distinct Regions of Human Carotid Plaques
- Author
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Nicolas Vuilleumier, Fabrizio Montecucco, François Mach, Federico Carbone, Karim J. Brandt, Kapka Miteva, Fabienne Burger, Rafaela F. da Silva, Daniela Baptista, and Aline Roth
- Subjects
Male ,0301 basic medicine ,Pathology ,Apolipoprotein B ,medicine.medical_treatment ,Carotid endarterectomy ,030204 cardiovascular system & hematology ,Extracellular Traps ,Neutrophil extracellular traps ,Cohort Studies ,Histones ,lcsh:Chemistry ,Vulnerable plaques ,0302 clinical medicine ,Anti-apoA-1 IgG ,Atherosclerosis ,lcsh:QH301-705.5 ,Spectroscopy ,ddc:616 ,General Medicine ,Plaque, Atherosclerotic ,Computer Science Applications ,Carotid Arteries ,Neutrophil elastase ,Immunohistochemistry ,Female ,medicine.medical_specialty ,Upstream and downstream (transduction) ,neutrophil extracellular traps ,Biology ,Article ,Catalysis ,Inorganic Chemistry ,03 medical and health sciences ,medicine ,Extracellular ,Humans ,Physical and Theoretical Chemistry ,Molecular Biology ,Aged ,Apolipoprotein A-I ,Organic Chemistry ,anti-apoA-1 IgG ,Colocalization ,030104 developmental biology ,lcsh:Biology (General) ,lcsh:QD1-999 ,Immunoglobulin G ,biology.protein ,atherosclerosis ,Leukocyte Elastase ,vulnerable plaques - Abstract
Background: Neutrophils accumulate in atherosclerotic plaques. Neutrophil extracellular traps (NET) were recently identified in experimental atherosclerosis and in complex human lesions. However, not much is known about the NET marker citrullinated histone-3 (H3Cit) expression and functionality in human carotid plaques. Moreover, the association between the proatherosclerotic autoantibody anti-apolipoprotein A-1 (anti-ApoA-1 IgG) and NET has never been investigated. Methods: Atherosclerotic plaques have been obtained from 36 patients with severe carotid stenosis that underwent carotid endarterectomy for severe carotid stenosis. Samples were sectioned into upstream and downstream regions from the same artery segment. Plaque composition and expression of NET markers neutrophil elastase (NE) and H3Cit were quantified by immunohistochemistry. H3Cit expression and function was evaluated by immunofluorescence and confocal analysis in a subset of patients. Results: Pathological features of vulnerable phenotypes were exacerbated in plaques developed at downstream regions, including higher accumulation of neutrophils and enhanced expression of NE and H3Cit, as compared to plaques from upstream regions. The H3Cit signal was also more intense in downstream regions, with significant extracellular distribution in spaces outside of neutrophils. The percentage of H3Cit colocalization with CD66b (neutrophils) was markedly lower in downstream portions of carotid plaques, confirming the extrusion of NET in this region. In agreement, the maximum distance of the H3Cit signal from neutrophils, extrapolated from vortex distance calculation in all possible directions, was also higher in downstream plaques. The serum anti-ApoA-1index positively correlated with the expression of H3Cit in downstream segments of plaques. Expression of the H3Cit signal outside of neutrophils and H3Cit maximal distance from CD66b-positive cells increased in plaques from serum positive anti-ApoA-1 patients compared with serum negative patients. Conclusion: NET elements are differentially expressed in upstream versus downstream regions of human carotid plaques and may be influenced by circulating levels of anti-ApoA-1 IgG. These findings could warrant the investigation of NET elements as potential markers of vulnerability.
- Published
- 2020
19. Telbivudine in chronic lymphocytic myocarditis and human parvovirus B19 transcriptional activity
- Author
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Dirk Lassner, Oliver Klein, Carsten Tschöpe, Sophie Van Linthout, Mohamed Abou-El-Enein, Burkert Pieske, Marzena Sosnowski, Kapka Miteva, Uwe Kühl, and Ahmed Elsanhoury
- Subjects
0301 basic medicine ,Myocarditis ,Necrosis ,biology ,business.industry ,Parvovirus ,CD3 ,030204 cardiovascular system & hematology ,Pharmacology ,medicine.disease ,biology.organism_classification ,medicine.disease_cause ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Telbivudine ,Heart failure ,Renin–angiotensin system ,medicine ,biology.protein ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business ,Oxidative stress ,medicine.drug - Abstract
Aims Myocarditis is often associated with parvovirus B19 (B19V) persistence, which can induce vascular damage. Based on the antiviral and anti-inflammatory properties of telbivudine, we aimed to evaluate its efficacy to protect B19V-infected endothelial cells in vitro and to treat chronic lymphocytic myocarditis patients with B19V transcriptional activity. Methods and results We evaluated the endothelial-protective potential of telbivudine in human microvascular endothelial cells-1, which were infected with B19V. Treatment with 10 ng/mL of telbivudine decreased the B19V-induced endothelial cell apoptosis and endothelial-to-mesenchymal transition. Along with this finding, telbivudine reduced the expression of transforming growth factor-β1 and of tenascin-C. The endothelial-protective properties of telbivudine were also found in tumour necrosis factor-α-stressed human microvascular endothelial cells-1. In addition, oxidative stress in angiotensin II-stressed and transforming growth factor-β1-stressed HL-1 cardiomyocytes and fibroblasts, respectively, was reduced upon telbivudine treatment, illustrating that telbivudine exerts multimodal protective effects. Based on these in vitro findings, four patients severely suffering from an endomyocardial biopsy-proven myocarditis associated with B19V transcriptional activity (VP1/VP2-mRNA positive) were treated with telbivudine (600 mg/dL) for 6 months in a single-patient-use approach. Follow-up biopsies 6 months after treatment showed that VP1/VP2-mRNA levels and CD3 cells decreased in all patients and were associated with an improvement in ejection fraction and New York Heart Association class. These findings were paralleled by a drop in tenascin-C expression as shown via matrix-assisted laser desorption ionization-imaging mass spectrometry. Conclusions Telbivudine exerts endothelial-protective effects in B19V-infected endothelial cells and improves chronic myocarditis associated with B19V transcriptional activity. These findings will be further evaluated in the clinical exploratory trial: the PreTopic study.
- Published
- 2018
20. Innate and adaptive immunity in atherosclerosis
- Author
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Rosalinda Madonna, Raffaele De Caterina, Kapka Miteva, and Sophie Van Linthout
- Subjects
0301 basic medicine ,Physiology ,030204 cardiovascular system & hematology ,Biology ,Extracellular matrix ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Immune system ,medicine ,Sterile inflammation ,Endothelial dysfunction ,Early onset ,Pharmacology ,Innate immune system ,Cholesterol ,Damage-associated molecular patterns ,Immune cells ,Atherosclerosis ,Acquired immune system ,medicine.disease ,NLRP3 inflammasome ,030104 developmental biology ,chemistry ,Immunology ,Molecular Medicine ,NLRP3 inflammasome activation - Abstract
Atherosclerosis is a chronic inflammatory disorder of the large and medium-size arteries characterized by the subendothelial accumulation of cholesterol, immune cells, and extracellular matrix. At the early onset of atherogenesis, endothelial dysfunction takes place. Atherogenesis is further triggered by the accumulation of cholesterol-carrying low-density lipoproteins, which acquire properties of damage-associated molecular patterns and thereby trigger an inflammatory response. Following activation of the innate immune response, mainly governed by monocytes and macrophages, the adaptive immune response is started which further promotes atherosclerotic plaque formation. In this review, an overview is given describing the role of damage-associated molecular patterns, NLRP3 inflammasome activation, and innate and adaptive immune cells in the atherogenesis process.
- Published
- 2018
21. Placenta‐Derived Adherent Stromal Cells Improve Diabetes Mellitus‐Associated Left Ventricular Diastolic Performance
- Author
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Wolfgang A. Linke, Sophie Van Linthout, Kathleen Pappritz, Nazha Hamdani, Lena Pinzur, Carsten Tschöpe, A Koschel, Kapka Miteva, Zami Aberman, and Irene Müller
- Subjects
0301 basic medicine ,Male ,endocrine system diseases ,Cardiac fibrosis ,Titin ,Diabetic Cardiomyopathies ,Placenta ,030204 cardiovascular system & hematology ,Placenta‐Derived Stem Cells ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Diabetes mellitus ,Translational Research Articles and Reviews ,Diastole ,Pregnancy ,Diabetic cardiomyopathy ,Ventricular Function ,Myocytes, Cardiac ,Cells, Cultured ,Tube formation ,Placenta‐expanded cell ,Diabetes ,General Medicine ,Vascular endothelial growth factor ,Passive force ,Female ,medicine.symptom ,medicine.drug ,medicine.medical_specialty ,Stromal cell ,Inflammation ,Mesenchymal Stem Cell Transplantation ,Diabetes Mellitus, Experimental ,03 medical and health sciences ,Arteriole ,Cardiac Disease ,medicine.artery ,Internal medicine ,Tissue Engineering and Regenerative Medicine ,medicine ,Human Umbilical Vein Endothelial Cells ,Animals ,Humans ,business.industry ,Cell Biology ,medicine.disease ,Streptozotocin ,Mice, Inbred C57BL ,030104 developmental biology ,Endocrinology ,chemistry ,business ,Developmental Biology - Abstract
Left ventricular (LV) diastolic dysfunction is among others attributed to cardiomyocyte stiffness. Mesenchymal stromal cells (MSC) have cardiac‐protective properties. We explored whether intravenous (i.v.) application of PLacenta‐eXpanded (PLX) MSC‐like cells (PLX) improves LV diastolic relaxation in streptozotocin (STZ)‐induced diabetic mice and investigated underlying mechanisms. Diabetes mellitus was induced by STZ application (50 mg/kg body weight) during five subsequent days. One week after the first STZ injection, PLX or saline were i.v. applied. Two weeks later, mice were hemodynamically characterized and sacrificed. At this early stage of diabetic cardiomyopathy with low‐grade inflammation and no cardiac fibrosis, PLX reduced LV vascular cell adhesion molecule‐1, transforming growth factor‐β1, and interferon‐γ mRNA expression, induced the percentage of circulating regulatory T cells, and decreased the splenic pro‐fibrotic potential in STZ mice. STZ + PLX mice exhibited higher LV vascular endothelial growth factor mRNA expression and arteriole density versus STZ mice. In vitro, hyperglycemic PLX conditioned medium restored the hyperglycemia‐impaired tube formation and adhesion capacity of human umbelical vein endothelial cells (HUVEC) via increasing nitric oxide (NO) bioavailability. PLX further induced the diabetes‐downregulated activity of the NO downstream protein kinase G, as well as of protein kinase A, in STZ mice, which was associated with a raise in phosphorylation of the titin isoforms N2BA and N2B. Concomitantly, the passive force was lower in single isolated cardiomyocytes from STZ + PLX versus from STZ mice, which led to an improvement of LV diastolic relaxation. We conclude that i.v. PLX injection improves diabetes mellitus‐associated diastolic performance via decreasing cardiomyocyte stiffness. Stem Cells Translational Medicine 2017;6:2135–2145
- Published
- 2017
22. Role of ubiquitin ligase PELI1 deficiency in atherosclerosis
- Author
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Kapka Miteva, Aline Roth, Daniel L. Baptista, Karim J. Brandt, Fabienne Burger, and François Mach
- Subjects
biology.protein ,Biology ,Cardiology and Cardiovascular Medicine ,Ubiquitin ligase ,Cell biology - Published
- 2021
23. Single-cell analysis uncovers osteoblast factor GDF10 as mediator of vascular smooth muscle cell phenotypic modulation associated with plaque rupture in human carotid artery disease
- Author
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Fabrizio Montecucco, François Mach, Daniel L. Baptista, Fabienne Burger, Aline Roth, R. F. Da Silva, Kapka Miteva, and Karim J. Brandt
- Subjects
Pathology ,medicine.medical_specialty ,Vascular smooth muscle ,Phenotypic modulation ,business.industry ,Cell ,Osteoblast ,medicine.disease ,medicine.anatomical_structure ,Mediator ,Single-cell analysis ,Carotid artery disease ,GDF10 ,medicine ,Cardiology and Cardiovascular Medicine ,business - Published
- 2021
24. Side specific predisposition to the vascular disease revealed by single-cell RNA-sequencing of aorta cells
- Author
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François Mach, Aline Roth, Fabienne Burger, R. Fernandes Da Silva, Karim J. Brandt, Kapka Miteva, and Daniel L. Baptista
- Subjects
Pathology ,medicine.medical_specialty ,Aorta ,medicine.anatomical_structure ,Vascular disease ,medicine.artery ,Cell ,medicine ,RNA ,Biology ,Cardiology and Cardiovascular Medicine ,medicine.disease - Published
- 2020
25. DEVELOPING LEARNING RESOURCES FOR WORKING WITH INTERACTIVE WHITEBOARDS AND TABLETS IN KINDERGARDEN
- Author
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Kapka Miteva
- Subjects
Multimedia ,Computer science ,Pedagogy ,computer.software_genre ,computer - Published
- 2017
26. Effect of monocytes on NLRP3 inflammasome activation in vascular smooth muscle cells phenotypic switch and foam cells formation in atherosclerosis
- Author
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Kapka Miteva, Aline Roth, Fabienne Burger, Daniel L. Baptista, R. F. Da Silva, François Mach, and Karim J. Brandt
- Subjects
Vascular smooth muscle ,Chemistry ,NLRP3 inflammasome activation ,Cardiology and Cardiovascular Medicine ,Phenotype ,Cell biology - Published
- 2020
27. CREATING DYNAMIC LEARNING ENVIRONMENT AT KINDERGARTEN THROUGH IMPLEMENTING EDUCATIONAL SOFTWARE AND DIDACTIC GAMES FROM EDU QUEST
- Author
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Kapka Miteva, Krasimira Dimitrova, Rumyana Karadimitrova, and Rumyana Papancheva
- Subjects
Multimedia ,Computer science ,Dynamic learning ,computer.software_genre ,computer ,Educational software - Published
- 2016
28. Human Endomyocardial Biopsy Specimen-Derived Stromal Cells Modulate Angiotensin II-Induced Cardiac Remodeling
- Author
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Irene Müller, Harald Stachelscheid, Sophie Van Linthout, Jochen Ringe, Kathleen Pappritz, Michael Sittinger, Marion Haag, Frank Spillmann, Kapka Miteva, and Carsten Tschöpe
- Subjects
Adult ,Male ,0301 basic medicine ,medicine.medical_specialty ,Stromal cell ,Cardiac fibrosis ,Biopsy ,Cardiomegaly ,Vascular Remodeling ,030204 cardiovascular system & hematology ,Ventricular Function, Left ,Muscle hypertrophy ,Immunomodulation ,03 medical and health sciences ,Paracrine signalling ,0302 clinical medicine ,Tissue Engineering and Regenerative Medicine ,Internal medicine ,Renin–angiotensin system ,medicine ,Animals ,Humans ,Myofibroblasts ,Ventricular remodeling ,Cell Proliferation ,business.industry ,Angiotensin II ,Myocardium ,Cell Biology ,General Medicine ,Fibroblasts ,medicine.disease ,Fibrosis ,Mice, Inbred C57BL ,Oxidative Stress ,030104 developmental biology ,Endocrinology ,Heart failure ,Cell Transdifferentiation ,Female ,Collagen ,Stromal Cells ,business ,Developmental Biology - Abstract
Cardiac-derived adherent proliferating cells (CardAPs) are cells derived from human endomyocardial biopsy specimens; they share several properties with mesenchymal stromal cells. The aims of this study were to evaluate whether intramyocardial injection of CardAPs modulates cardiac fibrosis and hypertrophy in a mouse model of angiotensin II (Ang II)-induced systolic heart failure and to analyze underlying mechanisms. Intramyocardial application of 200,000 CardAPs improved left ventricular function. This was paralleled by a decline in left ventricular remodeling, as indicated by a reduction in cardiac fibrosis and hypertrophy. CardAPs reduced the ratio of the left ventricle to body weight and cardiac myosin expression (heavy chain), and decreased the Ang II-induced phosphorylation state of the cardiomyocyte hypertrophy mediators Akt, extracellular-signal regulated kinase (ERK) 1, and ERK2. In accordance with the antifibrotic and antihypertrophic effects of CardAPs shown in vivo, CardAP supplementation with cardiac fibroblasts decreased the Ang II-induced reactive oxygen species production, α-SMA expression, fibroblast proliferation, and collagen production. Coculture of CardAPs with HL-1 cardiomyocytes downregulated the Ang II-induced expression of myosin in HL-1. All antifibrotic and antihypertrophic features of CardAPs were mediated in a nitric oxide- and interleukin (IL)-10-dependent manner. Moreover, CardAPs induced a systemic immunomodulation, as indicated by a decrease in the activity of splenic mononuclear cells and an increase in splenic CD4CD25FoxP3, CD4-IL-10, and CD8-IL-10 T-regulatory cells in Ang II mice. Concomitantly, splenocytes from Ang II CardAPs mice induced less collagen in fibroblasts compared with splenocytes from Ang II mice. We conclude that CardAPs improve Ang II-induced cardiac remodeling involving antifibrotic and antihypertrophic effects via paracrine actions and immunomodulatory properties. Significance Despite effective pharmacological treatment with angiotensin II type I receptor antagonists or angiotensin II-converting enzyme inhibitors, morbidity and mortality associated with heart failure are still substantial, prompting the search of novel therapeutic strategies. There is accumulating evidence supporting the use of cell therapy for cardiac repair. This study demonstrates that cells derived from human endomyocardial biopsies, cardiac-derived adherent proliferating cells (CardAPs), have the potential to reduce angiotensin II-induced cardiac remodeling and improve left ventricular function in angiotensin II mice. The mechanism involves antifibrotic and antihypertrophic effects via paracrine actions and immunomodulatory properties. These findings support the potential of CardAPs for the treatment of heart failure.
- Published
- 2016
29. Immunomodulation by adoptive regulatory T-cell transfer improves Coxsackievirus B3-induced myocarditis
- Author
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Konstantinos Savvatis, Kathleen Pappritz, Javier Díez, Sophie Van Linthout, Christine Brandt, Petra Reinke, Begoña López, Henry Fechner, Arantxa González, Carsten Tschöpe, Fengquan Dong, Susana Ravassa, Hans-Dieter Volk, Karin Klingel, Irene Müller, Kapka Miteva, and Bahtiyar Kerim
- Subjects
0301 basic medicine ,Chemokine ,Regulatory T cell ,viruses ,Inflammation ,030204 cardiovascular system & hematology ,Coxsackievirus ,Biochemistry ,Proinflammatory cytokine ,03 medical and health sciences ,0302 clinical medicine ,Genetics ,Medicine ,Molecular Biology ,biology ,business.industry ,Monocyte ,virus diseases ,biology.organism_classification ,030104 developmental biology ,medicine.anatomical_structure ,Monocyte differentiation ,Immunology ,cardiovascular system ,biology.protein ,Myelopoiesis ,medicine.symptom ,business ,Biotechnology - Abstract
Regulatory T (Treg) cells offer new therapeutic options for controlling undesired systemic and local immune responses. The aim of the current study was to determine the impact of therapeutic Treg administration on systemic and cardiac inflammation and remodeling in coxsackievirus B3 (CVB3) -induced myocarditis. Therefore, syngeneic Treg cells were applied intravenously in CVB3-infected mice 3 d after infection. Compared with CVB3 + PBS mice, CVB3 + Treg mice exhibited lower left ventricular (LV) chemokine expression, accompanied by reduced cardiac presence of proinflammatory Ly6ChighCCR2highCx3Cr1low monocytes and higher retention of proinflammatory Ly6CmidCCR2highCx3Cr1low monocytes in the spleen. In addition, splenic myelopoiesis was reduced in CVB3 + Treg compared with CVB3 + PBS mice. Coculture of Treg cells with splenocytes isolated from mice 3 d post-CVB3 infection further demonstrated the ability of Treg cells to modulate monocyte differentiation in favor of the anti-inflammatory Ly6ClowCCR2lowCx3Cr1high subset. Treg-mediated immunomodulation was paralleled by lower collagen 1 protein expression and decreased levels of soluble and insoluble collagen in LV of CVB3 + Treg compared with CVB3 + PBS mice. In agreement with these findings, LV systolic and diastolic function was improved in CVB3 + Treg mice compared with CVB3 + PBS mice. In summary, adoptive Treg transfer in the inflammatory phase of viral-induced myocarditis protects the heart against inflammatory damage and fibrosis via modulation of monocyte subsets.-Pappritz, K., Savvatis, K., Miteva, K., Kerim, B., Dong, F., Fechner, H., Muller, I., Brandt, C., Lopez, B., Gonzalez, A., Ravassa, S., Klingel, K., Diez, J., Reinke, P., Volk, H.-D., Van Linthout, S., Tschope, C. Immunomodulation by adoptive regulatory T-cell transfer improves Coxsackievirus B3-induced myocarditis.
- Published
- 2018
30. Pathogenic Role of the Damage-Associated Molecular Patterns S100A8 and S100A9 in Coxsackievirus B3–Induced Myocarditis
- Author
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Sophie Van Linthout, Dirk Lassner, Kathleen Pappritz, Burkert Pieske, Carsten Tschöpe, Uwe Kühl, Irene Müller, Thomas Vogl, Konstantinos Savvatis, Kapka Miteva, Patrick Most, and David Rohde
- Subjects
Male ,0301 basic medicine ,Chemokine ,viruses ,Chemokine CXCL2 ,Receptor for Advanced Glycation End Products ,030204 cardiovascular system & hematology ,Ventricular Function, Left ,Mice ,0302 clinical medicine ,Myocytes, Cardiac ,Mice, Knockout ,Gene knockdown ,biology ,virus diseases ,Middle Aged ,musculoskeletal system ,Enterovirus B, Human ,Myocarditis ,Neutrophil Infiltration ,Host-Pathogen Interactions ,Knockout mouse ,cardiovascular system ,Female ,RNA Interference ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,Signal Transduction ,Adult ,Coxsackievirus Infections ,Inflammation ,Transfection ,S100A9 ,S100A8 ,03 medical and health sciences ,Downregulation and upregulation ,medicine ,Animals ,Calgranulin B ,Humans ,Calgranulin A ,RNA, Messenger ,cardiovascular diseases ,business.industry ,Macrophages ,medicine.disease ,Fibrosis ,Mice, Inbred C57BL ,Disease Models, Animal ,Oxidative Stress ,RAW 264.7 Cells ,030104 developmental biology ,Case-Control Studies ,Immunology ,biology.protein ,business - Abstract
Background: The alarmins S100A8 and S100A9 are damage-associated molecular patterns, which play a pivotal role in cardiovascular diseases, inflammation, and viral infections. We aimed to investigate their role in Coxsackievirus B3 (CVB3)–induced myocarditis. Methods and Results: S100A8 and S100A9 mRNA expression was 13.0-fold ( P =0.012) and 5.1-fold ( P =0.038) higher in endomyocardial biopsies from patients with CVB3-positive myocarditis compared with controls, respectively. Elimination of CVB3 led to a downregulation of these alarmins. CVB3-infected mice developed an impaired left ventricular function and displayed an increased left ventricular S100A8 and S100A9 protein expression versus controls. In contrast, CVB3-infected S100A9 knockout mice, which are also a complete knockout for S100A8 on protein level, showed an improved left ventricular function, which was associated with a reduced cardiac inflammatory and oxidative response, and lower CVB3 copy number compared with wild-type CVB3 mice. Exogenous application of S100A8 to S100A9 knockout CVB3 mice induced a severe myocarditis similar to wild-type CVB3 mice. In CVB3-infected HL-1 cells, S100A8 and S100A9 enhanced oxidative stress and CVB3 copy number compared with unstimulated infected cells. In CVB3-infected RAW macrophages, both alarmins increased MIP-2 (macrophage inflammatory protein-2) chemokine expression, which was reduced in CVB3 S100A8 knockdown versus scrambled siRNA CVB3 cells. Conclusions: S100A8 and S100A9 aggravate CVB3-induced myocarditis and might serve as therapeutic targets in inflammatory cardiomyopathies.
- Published
- 2017
31. NOD2 (Nucleotide-Binding Oligomerization Domain 2) Is a Major Pathogenic Mediator of Coxsackievirus B3-Induced Myocarditis
- Author
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Uwe Kühl, Kathleen Pappritz, Markus M. Heimesaat, Stefan Bereswill, Sandra Pinkert, Sophie Van Linthout, Frank Spillmann, Konstantinos Savvatis, Henry Fechner, Heinz-Peter Schultheiss, Dirk Lassner, Kapka Miteva, Yu Xia, Irene Müller, Burkert Pieske, and Carsten Tschöpe
- Subjects
0301 basic medicine ,Male ,viruses ,Interleukin-1beta ,Nod2 Signaling Adaptor Protein ,Coxsackievirus Infections ,Apoptosis ,030204 cardiovascular system & hematology ,Biology ,Transfection ,Cell Line ,03 medical and health sciences ,0302 clinical medicine ,Mediator ,Downregulation and upregulation ,RNA interference ,NOD2 ,NLR Family, Pyrin Domain-Containing 3 Protein ,Animals ,Humans ,Genetic Predisposition to Disease ,cardiovascular diseases ,Mice, Knockout ,Innate immune system ,Myocardium ,Caspase 1 ,Pattern recognition receptor ,virus diseases ,Virology ,digestive system diseases ,Cell biology ,Enterovirus B, Human ,Up-Regulation ,CARD Signaling Adaptor Proteins ,Mice, Inbred C57BL ,Disease Models, Animal ,Myocarditis ,030104 developmental biology ,Phenotype ,Case-Control Studies ,Host-Pathogen Interactions ,cardiovascular system ,RNA Interference ,Signal transduction ,Cardiology and Cardiovascular Medicine ,Apoptosis Regulatory Proteins ,Signal Transduction - Abstract
Background: The cytoplasmatic pattern recognition receptor, NOD2 (nucleotide-binding oligomerization domain 2), belongs to the innate immune system and is among others responsible for the recognition of single-stranded RNA. With Coxsackievirus B3 (CVB3) being a single-stranded RNA virus, and the recent evidence that the NOD2 target, NLRP3 (NOD-like receptor family, pyrin domain containing 3) is of importance in the pathogenesis of CVB3-induced myocarditis, we aimed to unravel the role of NOD2 in CVB3-induced myocarditis. Methods and Results: Endomyocardial biopsy NOD2 mRNA expression was higher in CVB3-positive patients compared with patients with myocarditis but without evidence of persistent CVB3 infection. Left ventricular NOD2 mRNA expression was also induced in CVB3-induced myocarditis versus healthy control mice. NOD2 knockdown (−/− ) mice were rescued from the detrimental CVB3-mediated effects as shown by a reduced cardiac inflammation (less cardiac infiltrates and suppression of proinflammatory cytokines), cardiac fibrosis, apoptosis, lower CAR (Coxsackievirus and adenovirus receptor) expression and CVB3 copy number, and an improved left ventricular function in NOD2 −/− CVB3 mice compared with wild-type CVB3 mice. In agreement, NOD2 −/− decreased the CVB3-induced inflammatory response, CVB3 copy number, and apoptosis in vitro. NOD2 −/− was further associated with a reduction in CVB3-induced NLRP3 expression and activity as evidenced by lower ASC (apoptosis-associated speck-like protein containing a CARD) expression, caspase 1 activity, or IL-1β (interleukin-1β) protein expression under in vivo and in vitro CVB3 conditions. Conclusions: NOD2 is an important mediator in the viral uptake and inflammatory response during the pathogenesis of CVB3 myocarditis.
- Published
- 2017
32. LXR agonism improves TNF-α-induced endothelial dysfunction in the absence of its cholesterol-modulating effects
- Author
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Sophie Van Linthout, Verena Stangl, Heinz-Peter Schultheiss, Kapka Miteva, Carsten Tschöpe, Frank Spillmann, and Mario Lorenz
- Subjects
Male ,Benzylamines ,medicine.medical_specialty ,Hydrocarbons, Fluorinated ,Argininosuccinate synthase ,In Vitro Techniques ,Retinoid X receptor ,Nitric Oxide ,Benzoates ,Antioxidants ,chemistry.chemical_compound ,Enos ,Internal medicine ,Human Umbilical Vein Endothelial Cells ,medicine ,Animals ,Humans ,Endothelium ,RNA, Small Interfering ,Rats, Wistar ,Endothelial dysfunction ,Liver X receptor ,Aorta ,Liver X Receptors ,Caspase 7 ,Sulfonamides ,biology ,Caspase 3 ,Tumor Necrosis Factor-alpha ,Nitrotyrosine ,NADPH Oxidases ,Orphan Nuclear Receptors ,medicine.disease ,biology.organism_classification ,Rats ,Oxidative Stress ,Cholesterol ,Endocrinology ,chemistry ,NAD(P)H oxidase ,biology.protein ,lipids (amino acids, peptides, and proteins) ,P22phox ,Reactive Oxygen Species ,Cardiology and Cardiovascular Medicine - Abstract
Stimulation of the liver X receptor (LXR) is associated with anti-inflammatory and vascular-protective effects under hyperlipemic conditions. We examined whether LXR stimulation influences TNF-α-induced endothelial dysfunction under normolipemic conditions. Endothelium-dependent vasorelaxation of aortic rings was determined in an organ water bath. Human umbilical vein endothelial cells (HUVEC) were exposed to TNF-α (10 ng/ml) in the presence or absence of 5 μM of the LXR agonist T0901317 or GW3965 and changes in TNF-α-induced endothelial cell apoptosis, inflammation, oxidative stress, and NO metabolism were analyzed. T0901317 improved TNF-α-impaired endothelium-dependent relaxation of aortic rings in response to acetylcholine. T0901317 decreased the TNF-α-induced apoptosis and inflammation as indicated by a decrease in caspase 3/7 activity, VCAM-1 mRNA expression and subsequent mononuclear cell adhesion. Furthermore, T0901317 reduced the expression of the oxidative stress markers: AT1R, NOX4, and p22phox and normalized the TNF-α-induced NOX activity to basal levels. In line with the reduced AT1R expression, T0901317 impaired the Ang II responsiveness. T0901317 influenced NO metabolism as indicated by a decrease in TNF-α-upregulated arginase activity, a reversal of TNF-α-induced downregulation of argininosuccinate synthase mRNA expression and eNOS expression to basal levels and a raise in NO production. Furthermore, T0901317 decreased the TNF-α-induced superoxide and nitrotyrosine production, but did not upregulate the TNF-α-downregulated eNOS dimer/monomer ratio. Silencing of LXRβ, but not of LXRα, abrogated the anti-apoptotic effects of T0901317. We conclude that LXR agonism improves TNF-α-impaired endothelial function via its anti-apoptotic, anti-inflammatory, and anti-oxidative properties and its capacity to restore TNF-α-impaired NO bioavailability independent of its cholesterol-modulating effects.
- Published
- 2014
33. Pro-Angiogenic Effect of Endomyocardial Biopsy-Derived Cells for Cardiac Regeneration
- Author
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Marion Haag, Julia Ritterhoff, Alexandra Dimura, Kapka Miteva, Sophie Linthout, Carsten Tschope, Jochen Ringe, and Michael Sittinger
- Subjects
Health Information Management ,Health Informatics - Published
- 2013
34. Apolipoprotein A-I gene transfer exerts immunomodulatory effects and reduces vascular inflammation and fibrosis in ob/ob mice
- Author
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Carsten Tschöpe, Ilayaraja Muthuramu, Sophie Van Linthout, Kapka Miteva, Ruhul Amin, Bart De Geest, Frank Spillmann, and Burkert Pieske
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0301 basic medicine ,medicine.medical_specialty ,Apolipoprotein B ,HDL ,Clinical Biochemistry ,Spleen ,030204 cardiovascular system & hematology ,600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit ,Peripheral blood mononuclear cell ,Flow cytometry ,Immunomodulation ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,Fibrosis ,Internal medicine ,medicine ,Splenocyte ,Aorta ,Vascular fibrosis ,biology ,medicine.diagnostic_test ,business.industry ,Research ,Cell Biology ,medicine.disease ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,biology.protein ,lipids (amino acids, peptides, and proteins) ,business ,CD8 - Abstract
Background Obesity is associated with vascular inflammation, fibrosis and reduced high-density lipoproteins (HDL)-cholesterol. We aimed to investigate whether adenoviral gene transfer with human apolipoprotein (apo) A-I (Ad.A-I), the main apo of HDL, could exert immunomodulatory effects and counteract vascular inflammation and fibrosis in ob/ob mice. Methods Ad.A-I transfer was performed in 8 weeks (w) old ob/ob mice, which were sacrificed 7 w later. The aorta was excised for mRNA analysis and the spleen for splenocyte isolation for subsequent flow cytometry and co-culture with murine fibroblasts. HDL was added to mononuclear cells (MNC) and fibroblasts to assess their impact on adhesion capacity and collagen deposition, respectively. Results Ad.A-I led to a 1.8-fold (p
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- 2016
35. Role of Heart Rate Reduction in the Prevention of Experimental Heart Failure
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Peter Moritz Becher, Heinz-Peter Schultheiss, Carsten Tschöpe, Christin Zietsch, Dirk Westermann, Kapka Miteva, Konstantinos Savvatis, Sophie Van Linthout, Diana Lindner, and Bastian Schmack
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Male ,Cardiac function curve ,Cardiac output ,medicine.medical_specialty ,Cyclic Nucleotide-Gated Cation Channels ,Apoptosis ,Sensitivity and Specificity ,Drug Administration Schedule ,Statistics, Nonparametric ,Article ,Mice ,Random Allocation ,Ventricular Dysfunction, Left ,Afterload ,Heart Rate ,Tachycardia ,Internal medicine ,In Situ Nick-End Labeling ,Internal Medicine ,medicine ,Animals ,Ivabradine ,Metoprolol ,Heart Failure ,Dose-Response Relationship, Drug ,Ventricular Remodeling ,business.industry ,Angiotensin II ,Benzazepines ,medicine.disease ,Adrenergic beta-1 Receptor Antagonists ,Immunohistochemistry ,Mice, Inbred C57BL ,Disease Models, Animal ,Treatment Outcome ,Blood pressure ,Heart failure ,Multivariate Analysis ,Cardiology ,Cytokines ,business ,medicine.drug - Abstract
To investigate whether heart rate reduction via I f -channel blockade and β-receptor blockade prevents left ventricular (LV) dysfunction, we studied ivabradine and metoprolol in angiotensin II–induced heart failure. Cardiac dysfunction in C57BL/6J mice was induced by implantation of osmotic pumps for continuous subcutaneous dosing of angiotensin II (1.8 mg/kg per day SC) over a period of 3 weeks. Ivabradine (10 mg/kg per day) and metoprolol (90 mg/kg per day), which resulted in similar heart rate reduction, or placebo treatments were simultaneously started with infusion of angiotensin II. After 3 weeks, LV function was estimated by conductance catheter technique, cardiac remodeling assessed by estimation of cardiac hypertrophy, fibrosis, and inflammatory stress response by immunohistochemistry or PCR, respectively. Compared with controls, angiotensin II infusion resulted in hypertension in impaired systolic (LV contractility, stroke volume, end systolic elastance, afterload, index of arterial-ventricular coupling, and cardiac output; P P P P f -channel inhibition.
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- 2012
36. Mesenchymal Stromal Cells: A Promising Cell Source for the Treatment of Inflammatory Cardiomyopathy
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Kapka Miteva, S Van Linthout, H.-P. Schultheiss, and Carsten Tschöpe
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Myocarditis ,Cardiac fibrosis ,Transgene ,Cell ,Cardiomyopathy ,Inflammation ,Mesenchymal Stem Cell Transplantation ,Cell Movement ,Drug Discovery ,medicine ,Animals ,Humans ,Transgenes ,Pharmacology ,Clinical Trials as Topic ,business.industry ,Mesenchymal stem cell ,Mesenchymal Stem Cells ,medicine.disease ,Treatment Outcome ,medicine.anatomical_structure ,Immunology ,Cytokines ,medicine.symptom ,business ,Cardiomyocyte apoptosis - Abstract
Inflammatory cardiomyopathy is associated with a diffuse inflammation in the heart accompanied with cardiac fibrosis, cardiomyocyte apoptosis, and reduced capillary density. On the other hand, mesenchymal stromal cells (MSCs) have immunomodulatory, anti-fibrotic, anti-apoptotic, and pro-angiogenic features, making them attractive candidates for the treatment of inflammatory cardiomyopathy. The potential of MSC application for the treatment of myocarditis is supported by their beneficial effects in experimental models of acute and chronic inflammatory cardiomopathy. This review summarizes the cardioprotective features of MSCs and describes how MSCs are primed by the inflammatory environment to exert their protective effects. In view of clinical translation, searching for the optimal source of MSC and delivery route, allowing efficient and non-invasive cell application, the differences between MSCs of distinct origin and between diverse routes of application are outlined.
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- 2011
37. Mesenchymal stem cells improve murine acute coxsackievirus B3-induced myocarditis
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Michael Sittinger, Jun Peng, Katrin Warstat, Carsten Tschöpe, K. Savvatis, Jochen Ringe, S Van Linthout, Kapka Miteva, Caroline Schmidt-Lucke, and H.P. Schultheiss
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Myocarditis ,T cell ,viruses ,Priming (immunology) ,Coxsackievirus Infections ,Apoptosis ,Mesenchymal Stem Cell Transplantation ,Virus Replication ,Interferon-gamma ,Mice ,Immune system ,Basic Science ,Interferon ,medicine ,Coxsackievirus ,Animals ,Humans ,Ventricular Function ,Interferon gamma ,Viability assay ,cardiovascular diseases ,business.industry ,Mesenchymal stem cell ,virus diseases ,Immunoregulation ,Nitric oxide ,Mesenchymal Stem Cells ,medicine.disease ,Enterovirus B, Human ,Mice, Inbred C57BL ,medicine.anatomical_structure ,Immunology ,Cancer research ,cardiovascular system ,Interferon-γ ,Cardiology and Cardiovascular Medicine ,business ,medicine.drug - Abstract
Aims Coxsackievirus B3 (CVB3)-induced myocarditis, initially considered a sole immune-mediated disease, also results from a direct CVB3-mediated injury of the cardiomyocytes. Mesenchymal stem cells (MSCs) have, besides immunomodulatory, also anti-apoptotic features. In view of clinical translation, we first analysed whether MSCs can be infected by CVB3. Next, we explored whether and how MSCs could reduce the direct CVB3-mediated cardiomyocyte injury and viral progeny release, in vitro, in the absence of immune cells. Finally, we investigated whether MSC application could improve murine acute CVB3-induced myocarditis. Methods and results Phase contrast pictures and MTS viability assay demonstrated that MSCs did not suffer from CVB3 infection 4-12-24-48 h after CVB3 infection. Coxsackievirus B3 RNA copy number decreased in this time frame, suggesting that no CVB3 replication took place. Co-culture of MSCs with CVB3-infected HL-1 cardiomyocytes resulted in a reduction of CVB3-induced HL-1 apoptosis, oxidative stress, intracellular viral particle production, and viral progeny release in a nitric oxide (NO)-dependent manner. Moreover, MSCs required priming via interferon-γ (IFN-γ) to exert their protective effects. In vivo, MSC application improved the contractility and relaxation parameters in CVB3-induced myocarditis, which was paralleled with a reduction in cardiac apoptosis, cardiomyocyte damage, left ventricular tumour necrosis factor-α mRNA expression, and cardiac mononuclear cell activation. Mesenchymal stem cells reduced the CVB3-induced CD4- and CD8- T cell activation in an NO-dependent way and required IFN-γ priming. Conclusion We conclude that MSCs improve murine acute CVB3-induced myocarditis via their anti-apoptotic and immunomodulatory properties, which occur in an NO-dependent manner and require priming via IFN-γ.
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- 2010
38. High-density lipoproteins reduce endothelial-to-mesenchymal transition
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Sophie Van Linthout, Burkert Pieske, Kapka Miteva, Frank Spillmann, and Carsten Tschöpe
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medicine.medical_specialty ,Epithelial-Mesenchymal Transition ,Phase contrast microscopy ,High density ,Biology ,Transfection ,law.invention ,Flow cytometry ,Transforming Growth Factor beta1 ,law ,Fibrosis ,Antigens, CD ,Internal medicine ,medicine ,Humans ,Cell Shape ,Cells, Cultured ,medicine.diagnostic_test ,Transition (genetics) ,Cadherin ,Mesenchymal stem cell ,Endothelial Cells ,Scavenger Receptors, Class B ,medicine.disease ,Cadherins ,Actins ,Cell biology ,Endocrinology ,Phenotype ,RNA Interference ,Collagen ,Phosphatidylinositol 3-Kinase ,Cardiology and Cardiovascular Medicine ,Lipoproteins, HDL ,Transforming growth factor ,Signal Transduction - Abstract
Objective— Endothelial-to-mesenchymal transition is an inflammation-induced process by which endothelial cells can transdifferentiate into fibroblasts. Based on the endothelial-protective and antifibrotic effects of high-density lipoproteins (HDL), we aimed to investigate whether HDL can reduce endothelial-to-mesenchymal transition. Approach and Results— Therefore, human aortic endothelial cells were stimulated with the profibrotic factor transforming growth factor (TGF)-β1 in the presence or absence of HDL. Their impact on the transition of endothelial cells to mesenchymal-like cells was analyzed. Phase contrast microscopy demonstrated that HDL abrogated the TGF-β1–induced spindle-shape morphology in human aortic endothelial cells. Furthermore, HDL decreased the TGF-β1–mediated induction of α-smooth muscle actin expression and concomitant loss in endothelial cadherin expression, as shown by immunofluorescence staining and flow cytometry. In addition, HDL decreased the TGF-β1–induced collagen deposition in human aortic endothelial cells involving the scavenger receptor class B, type 1 and downstream phosphatidyl inositol-3-kinase following the findings that the HDL-mediated reduction was abrogated by scavenger receptor class B, type 1 siRNA knockdown and phosphatidyl inositol-3-kinase inhibition, respectively. The HDL-mediated reduction in endothelial-to-mesenchymal transition was associated with an induction of the inhibitory Smad, Smad 7. Conclusions— We provide the first in vitro evidence that the endothelial-protective and antifibrotic effects of HDL include the reduction in endothelial-to-mesenchymal transition.
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- 2014
39. Crosstalk between fibroblasts and inflammatory cells
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Carsten Tschöpe, Sophie Van Linthout, and Kapka Miteva
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Physiology ,medicine.medical_treatment ,Cell ,Inflammation ,Biology ,Adaptive Immunity ,Extracellular matrix ,Immune system ,Physiology (medical) ,medicine ,Animals ,Humans ,Fibroblast ,Heart Failure ,biochemical phenomena, metabolism, and nutrition ,Fibroblasts ,Acquired immune system ,Cell biology ,Crosstalk (biology) ,medicine.anatomical_structure ,Cytokine ,Immune System ,Cytokines ,medicine.symptom ,Cardiology and Cardiovascular Medicine - Abstract
Fibroblasts, which are traditionally recognized as a quiescent cell responsible for extracellular matrix production, are more and more appreciated as an active key player of the immune system. This review describes how fibroblasts and immune cells reciprocally influence the pathogenesis of fibrosis. An overview is given how fibroblasts are triggered by components of the innate and adaptive immunity on the one hand and how fibroblasts modulate immune cell behaviour via conditioning the cellular and cytokine microenvironment on the other hand. Finally, latest insights into the role of cardiac fibroblasts in the orchestration of inflammatory cell infiltration in the heart, and their impact on heart failure, are outlined.
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- 2014
40. Staurosporine-induced differentiation of the RGC-5 cell line leads to apoptosis and cell death at the lowest differentiating concentration
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Sven Schnichels, Sophie Van Linthout, Peter Szurman, M. Schultheiss, Katrin Warstat, Martin S. Spitzer, and Kapka Miteva
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Retinal Ganglion Cells ,Programmed cell death ,Cell Survival ,Cellular differentiation ,Apoptosis ,Biology ,Cell morphology ,Polymerase Chain Reaction ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,medicine ,Staurosporine ,Humans ,Microscopy, Phase-Contrast ,Viability assay ,Propidium iodide ,RNA, Messenger ,Annexin A5 ,Enzyme Inhibitors ,Fluorescent Antibody Technique, Indirect ,Cell Proliferation ,bcl-2-Associated X Protein ,Caspase 7 ,Cell Death ,Cell growth ,Caspase 3 ,Cell Differentiation ,Flow Cytometry ,Sensory Systems ,Cell biology ,Ophthalmology ,chemistry ,Microscopy, Fluorescence ,Proto-Oncogene Proteins c-bcl-2 ,Dactinomycin ,medicine.drug - Abstract
Supplementation of staurosporine is the method of choice for differentiating the solely existing retinal ganglion cell (RGC)-5 cell line. This differentiation was initially claimed to be in the absence of apoptosis, but some publications supposed the induction of apoptosis during staurosporine induced RGC-5 differentiation. In respect to these inconsistencies in the literature, we investigated in detail whether RGC-5 cell differentiation by staurosporine induces apoptosis or not. Amounts of 50 nM, 200 nM, 300 nM, and 600 nM of staurosporine were supplemented on RGC-5 cells for 24 h. Cell morphology and cell death, via propidium iodide staining, were evaluated with phase contrast and fluorescence microscopy, respectively. Cell amount, cell proliferation, and cell viability were analyzed by crystal violet staining, CFSE flow cytometry, and MTS assay, respectively. Apoptosis was determined by analyzing caspase 3/7 activity, Annexin-V+/ 7AAD- cells and the quotient of Bax to Bcl-2 mRNA expression via caspase 3/7 activity assay, flow cytometry, and real-time PCR, respectively. RGC-5 cells started to change their morphology and their expression of neuronal markers at 50 nM of staurosporine. This was associated with apoptosis and cell death, as indicated by a 2.1-fold (p
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- 2011
41. Human cardiac-derived adherent proliferating cells reduce murine acute Coxsackievirus B3-induced myocarditis
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Marion Haag, Sophie Van Linthout, Peter Moritz Becher, Heinz-Peter Schultheiss, Jun Peng, Dirk Westermann, Carsten Tschöpe, K. Savvatis, Jochen Ringe, Martina Seifert, Kapka Miteva, Michael Sittinger, and Katrin Warstat
- Subjects
RNA viruses ,Cell Transplantation ,viruses ,Cardiomyopathy ,lcsh:Medicine ,Apoptosis ,Cardiovascular ,T-Lymphocytes, Regulatory ,Mice ,Viral classification ,Molecular Cell Biology ,Cytotoxic T cell ,Receptor ,lcsh:Science ,Enterovirus ,Multidisciplinary ,CD55 Antigens ,virus diseases ,Interleukin-10 ,Myocarditis ,Infectious Diseases ,Injections, Intravenous ,cardiovascular system ,Medicine ,Receptors, Virus ,Cellular Types ,Cardiomyopathies ,Research Article ,Coxsackie and Adenovirus Receptor-Like Membrane Protein ,Cell Survival ,Immune Cells ,Coxsackievirus Infections ,Biology ,Coxsackievirus ,Nitric Oxide ,Microbiology ,Immunomodulation ,Interferon-gamma ,Virology ,Cell Adhesion ,medicine ,Animals ,Humans ,Cell Proliferation ,Heart Failure ,Myocytes ,Acute Cardiovascular Problems ,Myocardium ,Mesenchymal stem cell ,lcsh:R ,medicine.disease ,biology.organism_classification ,Myocardial Contraction ,Heart failure ,Immunology ,lcsh:Q - Abstract
BACKGROUND: Under conventional heart failure therapy, inflammatory cardiomyopathy typically has a progressive course, indicating a need for alternative therapeutic strategies to improve long-term outcomes. We recently isolated and identified novel cardiac-derived cells from human cardiac biopsies: cardiac-derived adherent proliferating cells (CAPs). They have similarities with mesenchymal stromal cells, which are known for their anti-apoptotic and immunomodulatory properties. We explored whether CAPs application could be a novel strategy to improve acute Coxsackievirus B3 (CVB3)-induced myocarditis. METHODOLOGY/PRINCIPAL FINDINGS: To evaluate the safety of our approach, we first analyzed the expression of the coxsackie- and adenovirus receptor (CAR) and the co-receptor CD55 on CAPs, which are both required for effective CVB3 infectivity. We could demonstrate that CAPs only minimally express both receptors, which translates to minimal CVB3 copy numbers, and without viral particle release after CVB3 infection. Co-culture of CAPs with CVB3-infected HL-1 cardiomyocytes resulted in a reduction of CVB3-induced HL-1 apoptosis and viral progeny release. In addition, CAPs reduced CD4 and CD8 T cell proliferation. All CAPs-mediated protective effects were nitric oxide- and interleukin-10-dependent and required interferon-γ. In an acute murine model of CVB3-induced myocarditis, application of CAPs led to a decrease of cardiac apoptosis, cardiac CVB3 viral load and improved left ventricular contractility parameters. This was associated with a decline in cardiac mononuclear cell activity, an increase in T regulatory cells and T cell apoptosis, and an increase in left ventricular interleukin-10 and interferon-γ mRNA expression. CONCLUSIONS: We conclude that CAPs are a unique type of cardiac-derived cells and promising tools to improve acute CVB3-induced myocarditis.
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- 2011
42. Identification of noncytotoxic and IL-10-producing CD8+AT2R+ T cell population in response to ischemic heart injury
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Jian An Wang, Elena Kaschina, Wassim Altarche-Xifro, Jun Li, Kapka Miteva, Thomas Unger, Svetlana Slavic, Anna Skorska, Jun Dong, Caterina Curato, Andreas Thiel, Gustav Steinhoff, Hans Imboden, and Ulrike Muscha Steckelings
- Subjects
Male ,medicine.medical_specialty ,medicine.medical_treatment ,T cell ,Immunology ,Population ,Myocardial Infarction ,Myocardial Ischemia ,Fluorescent Antibody Technique ,Gene Expression ,Cell Separation ,CD8-Positive T-Lymphocytes ,Receptor, Angiotensin, Type 2 ,Interleukin 21 ,Immune system ,T-Lymphocyte Subsets ,Internal medicine ,Immunology and Allergy ,Medicine ,Animals ,Rats, Wistar ,education ,education.field_of_study ,business.industry ,Reverse Transcriptase Polymerase Chain Reaction ,Myocardium ,Acquired immune system ,Flow Cytometry ,Molecular biology ,Interleukin-10 ,Rats ,Interleukin 10 ,Endocrinology ,Cytokine ,medicine.anatomical_structure ,business ,CD8 - Abstract
Emerging evidence suggests a cardioprotective role of the angiotensin AT2R, albeit the underlying cellular mechanisms are not well understood. We aimed in this article to elucidate a potential role of cardiac angiotensin AT2R in regulating cellular immune response to ischemic heart injury. Seven days after myocardial infarction in rats, double-immunofluorescence staining showed that AT2R was detected in a fraction of CD8+ T cells infiltrating in the peri-infarct myocardium. We developed a method that allowed the isolation of myocardial infiltrating CD8+AT2R+ T cells using modified MACS, and further characterization and purification with flow cytometry. Although the CD8+AT2R− T cells exhibited potent cytotoxicity to both adult and fetal cardiomyocytes (CMs), the CD8+AT2R+ T cells were noncytotoxic to these CMs. The CD8+AT2R+ T cells were characterized by upregulated IL-10 and downregulated IL-2 and INF-γ expression when compared with CD8+AT2R− T cells. We further showed that IL-10 gene expression was enhanced in CD8+ T cells on in vitro AT2R stimulation. Importantly, in vivo AT2R activation engendered an increment of CD8+AT2R+ T cells and IL-10 production in the ischemic myocardium. In addition, intramyocardial transplantation of CD8+AT2R+ T cells (versus CD8+AT2R−) led to reduced ischemic heart injury. Moreover, the CD8+AT2R+ T cell population was also demonstrated in human peripheral blood. Thus, we have defined the cardioprotective CD8+AT2R+ T cell population, which increases during ischemic heart injury and contributes to maintaining CM viability and providing IL-10, hence revealing an AT2R-mediated cellular mechanism in modulating adaptive immune response in the heart.
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- 2010
43. ‘Mesenchymal stem cells improve murine acute coxsackievirus B3-induced myocarditis’ [Eur Heart J 2011;32(17):2168-2178, doi:10.1093/eurheartj/ehq467]
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Jochen Ringe, Katrin Warstat, Caroline Schmidt-Lucke, Carsten Tschöpe, K. Savvatis, H.-P. Schultheiss, Michael Sittinger, Jun Peng, S Van Linthout, and Kapka Miteva
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Pathology ,medicine.medical_specialty ,Myocarditis ,Coxsackievirus b3 ,business.industry ,Mesenchymal stem cell ,medicine ,Corrigendum ,Cardiology and Cardiovascular Medicine ,medicine.disease ,business - Abstract
There were several errors present in figure 1 of this manuscript. In figure 1A the same image is presented for non-infected MSC 48h as for CVB3-infected 48h. The image of CVB3-infected 48h is wrongly positioned in place of CVB3-infected 24h. In addition, appropriate headings were not displayed above the images of Figure 1A. The correct figure is presented below: The authors apologize for the error.
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- 2013
44. Mesenchymal Stromal Cells but Not Cardiac Fibroblasts Exert Beneficial Systemic Immunomodulatory Effects in Experimental Myocarditis
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P.M. Becher, Kathleen Pappritz, Andreas Kurtz, Gerhard Fusch, Carsten Tschöpe, Jochen Ringe, Konstantinos Savvatis, Sophie Van Linthout, Ursula Rauch, Joerg C. Schefold, Karin Klingel, Dirk Westermann, Heinz-Peter Schultheiss, Kapka Miteva, and Alice Weithauser
- Subjects
CD4-Positive T-Lymphocytes ,Viral Diseases ,Interleukin-1beta ,Cardiomyopathy ,CD8-Positive T-Lymphocytes ,Cardiovascular ,Mice ,Bone Marrow ,Immune Response ,Cells, Cultured ,In Situ Hybridization ,Multidisciplinary ,T Cells ,FOXP3 ,Forkhead Transcription Factors ,Flow Cytometry ,Myocarditis ,Infectious Diseases ,Cytokines ,Medicine ,Tumor necrosis factor alpha ,medicine.symptom ,Cardiomyopathies ,Research Article ,Immune Cells ,Science ,Immunology ,Inflammation ,Biology ,Proinflammatory cytokine ,Immune system ,medicine ,Animals ,Humans ,Heart Failure ,Interleukin-6 ,Tumor Necrosis Factor-alpha ,Mesenchymal stem cell ,Hemodynamics ,Immunity ,Immunoregulation ,Mesenchymal Stem Cells ,Fibroblasts ,medicine.disease ,Mice, Inbred C57BL ,Immune System - Abstract
Systemic application of mesenchymal stromal cells (MSCs) in inflammatory cardiomyopathy exerts cardiobeneficial effects. The mode of action is unclear since a sufficient and long-acting cardiac homing of MSCs is unlikely. We therefore investigated the regulation of the immune response in coxsackievirus B3 (CVB3)-induced acute myocarditis after intravenous application of MSCs. Wildtype mice were infected with CVB3 and treated with either PBS, human MSCs or human cardiac fibroblasts intravenously 1 day after infection. Seven days after infection, MSCs could be detected in the spleen, heart, pancreas, liver, lung and kidney, whereby the highest presence was observed in the lung. MSCs increased significantly the myocardial expression of HGF and decreased the expression of the proinflammatory cytokines TNFα, IL1β and IL6 as well as the severity of myocarditis and ameliorated the left ventricular dysfunction measured by conductance catheter. MSCs upregulated the production of IFNγ in CD4+ and CD8+ cells, the number of IL10-producing regulatory T cells and the apoptosis rate of T cells in the spleen. An increased number of CD4+CD25+FoxP3 could be found in the spleen as well as in the circulation. In contrast, application of human cardiac fibroblasts had no effect on the severity of myocarditis and the systemic immune response observed after MSCs-administration. In conclusion, modulation of the immune response in extracardiac organs is associated with cardiobeneficial effects in experimental inflammatory cardiomyopathy after systemic application of MSCs.
- Published
- 2012
45. Down-regulation of endothelial TLR4 signalling after apo A-I gene transfer contributes to improved survival in an experimental model of lipopolysaccharide-induced inflammation
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Heinz-Peter Schultheiss, Federico Quaini, Carsten Tschöpe, Wolfram Doehner, Felicitas Escher, Marco Meloni, Markus Tölle, Eline Van Craeyveld, Kapka Miteva, Jun Peng, Bart De Geest, Sophie Van Linthout, Aysun Subasiguller, Gallia Graiani, and Frank Spillmann
- Subjects
Lipopolysaccharides ,Male ,medicine.medical_specialty ,Lipopolysaccharide ,Apolipoprotein B ,Endothelial cells ,Down-Regulation ,Inflammation ,Biology ,Cell Line ,chemistry.chemical_compound ,Mice ,High-density lipoprotein ,Internal medicine ,Drug Discovery ,medicine ,Animals ,Humans ,Genetics(clinical) ,Lung ,Gene transfer ,Genetics (clinical) ,Regulation of gene expression ,Medicine(all) ,Apolipoprotein A-I ,Cholesterol ,Gene Transfer Techniques ,nutritional and metabolic diseases ,Toll-like receptor 4 ,Survival Analysis ,Mice, Inbred C57BL ,Endocrinology ,chemistry ,Gene Expression Regulation ,Immunology ,TLR4 ,biology.protein ,Molecular Medicine ,Original Article ,lipids (amino acids, peptides, and proteins) ,medicine.symptom ,Lipoproteins, HDL ,Lipoprotein ,Signal Transduction - Abstract
The protective effects of high-density lipoprotein (HDL) under lipopolysaccharide (LPS) conditions have been well documented. Here, we investigated whether an effect of HDL on Toll-like receptor 4 (TLR4) expression and signalling may contribute to its endothelial-protective effects and to improved survival in a mouse model of LPS-induced inflammation and lethality. HDL cholesterol increased 1.7-fold (p
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46. Cardiotrophin-1 Deficiency Abrogates Atherosclerosis Progression
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Rodrigo A. Fraga-Silva, Fabienne Burger, Fabrizio Montecucco, Daniela Baptista, Mohamed Asrih, Kapka Miteva, François Mach, Karim J. Brandt, Nikolaos Stergiopulos, and Aline Roth
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0301 basic medicine ,Male ,Atherosclerosis/blood ,lcsh:Medicine ,030204 cardiovascular system & hematology ,0302 clinical medicine ,lcsh:Science ,Aorta ,ddc:616 ,Multidisciplinary ,Cytokines/genetics ,Interleukin ,monocyte chemotactic protein-3 ,medicine.anatomical_structure ,messenger-rna ,CXCL5 ,Disease Progression ,Cytokines ,lipids (amino acids, peptides, and proteins) ,hypertrophy ,medicine.medical_specialty ,Cardiotrophin 1 ,Regulatory B cells ,regulatory t-cells ,Spleen ,heart ,Article ,interleukin-6 synthesis ,Aorta/pathology ,03 medical and health sciences ,Paracrine signalling ,Immune system ,Apolipoproteins E ,medicine.artery ,Internal medicine ,Atherosclerosis/pathology ,expression ,medicine ,Animals ,increases collagen content ,intercellular-adhesion molecule-1 ,low-density-lipoprotein ,business.industry ,Interleukins ,lcsh:R ,Atherosclerosis ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,Endocrinology ,Atherosclerosis/genetics ,lcsh:Q ,business ,Apolipoproteins E/genetics ,Gene Deletion - Abstract
Cardiotrophin-1 (CT-1) is associated with cardiovascular (CV) diseases. We investigated the effect of CT-1 deficiency in the development and progression of atherosclerosis in double knockout Apoe−/−ct-1−/− mice. Apoe−/− C57Bl/6 or Apoe−/−ct-1−/− C57Bl/6 mice were fed a normal chow diet (NCD) or a high-cholesterol diet (HCD). After sacrifice, serum triglycerides, total cholesterol, low-density lipoprotein cholesterol (LDL-C), free fatty acids and systemic paracrine factors were measured. Intraplaque lipid and collagen content were quantified in the aortic sections. Immune cell populations in spleen, lymph nodes and aorta were analysis by flow cytometry. Apoe−/−ct-1−/− mice in accelerated atherosclerosis exhibited a reduction of total cholesterol, LDL-C, atherosclerotic plaques size in the aortic root and in the abdominal aorta and improved plaque stability in comparison to Apoe−/− mice. CT-1 deficiency in Apoe−/− mice on (HCD) promoted atheroprotective immune cell responses, as demonstrated by a rise in plasma anti-inflammatory immune cell populations (regulatory T cells, Tregs; regulatory B cells, Bregs and B1a cells) and atheroprotective IgM antibodies. CT-1 deficiency in advanced atherosclerosis mediated regulation of paracrine factors, such as interleukin (IL)-3, IL-6, IL-9, IL-15, IL-27, CXCL5, MCP-3, MIP-1α and MIP-1β. In a model of advanced atherosclerosis, CT-1 deficiency induced anti-inflammatory and atheroprotective effects which resulted in abrogation of atheroprogression.
47. LXR AGONISM IMPROVES TNF-ALPHA-INDUCED ENDOTHELIAL DYSFUNCTION
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Heinz-Peter Schultheiss, Frank Spillmann, Carsten Tschöpe, Sophie Van Linthout, Mario Lorenz, Kapka Miteva, and Verena Stangl
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business.industry ,Medicine ,Agonism ,Tumor necrosis factor alpha ,Pharmacology ,Endothelial dysfunction ,Liver X receptor ,business ,medicine.disease ,Cardiology and Cardiovascular Medicine - Full Text
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