Exercise Reverses Dysregulated Gene Expression in a Desmoplakin Haplo-insufficient Mouse Model of Arrhythmogenic Cardiomyopathy
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE129962 | GEO | 2020/04/29
REPOSITORIES: GEO
Similar Datasets
Project description:To delineate the role of the epicardium, the initial site of presentation of the ACM phenotype, the Dsp gene, encoding desmosome protein desmoplakin (DSP) was conditionally deleted in the mouse epicardial cells under the transcriptional regulation of Wilms tumor 1 (Wt1) locus. Single cell RNA sequencing (scRNA-Seq) of ~ 40,000 tagged epicardial-derived cells (EDCs), isolated using the dual reporter R26mT/mG mice, showed an increased number of EDCs expressing unique molecular identifiers of fibroblasts as well as a unique subset of epicardial-derived fibroblasts expressing pro-fibrotic genes in the Wt1-Cre: R26mT/mG: Dsp mice. Analysis of pseudo-bulk RNA-Seq data identified ~ 800 differentially expressed genes (DEGs), which were predominantly involved in epithelial-mesenchymal transition (EMT). The DEGs were the targets of TGFB1 among other trophic/mitotic factors, whose activation was verified by immunohistochemistry and quantification of transcript levels of selected TGBF1 pathway genes. Retro-mapping of the DEGs to the cell clusters, identified by scRNA-Seq, denoted epicardial-derived fibroblasts and to a lesser extent the epithelial cells as the main sources of paracrine factors in the myocardium of Wt1-Cre: R26mT/mG: Dsp mice.
2021-04-13 | GSE151084 | GEO
Project description:Exercise Reverses Dysregulated Gene Expression in a Desmoplakin Haplo-insufficient Mouse Model of Arrhythmogenic Cardiomyopathy
| PRJNA533295 | ENA
Project description:Background: Arrhythmogenic cardiomyopathy (ACM) is a genetic autosomal disease characterized by abnormal cell-cell adhesion, cardiomyocyte death, progressive fibro-adipose replacement of the myocardium, arrhythmias and sudden death. Several different cell types contribute to the pathogenesis of ACM, including, as recently described, cardiac stromal cells (CStCs). In the present study, we aim to identify ACM-specific expression profiles of human CStCs derived from endomyocardial biopsies of ACM patients and healthy individuals employing TaqMan Low Density Arrays for miRNA expression profiling, and high throughput sequencing for gene expression quantification. Results: We identified 5 miRNAs and 272 genes as significantly differentially expressed. Both the differentially expressed genes as well as the target genes of the ACM-specific miRNAs were found to be enriched in cell adhesion related biological processes. Functional similarity and protein interaction based network analyses performed on the identified deregulated genes, miRNA targets and known ACM-causative genes revealed clusters of highly related genes involved in cell adhesion, extracellular matrix organization, lipid transport and ephrin receptor signaling. Conclusions: We determined for the first time the coding and non-coding transcriptome characteristic of ACM cardiac stromal cells, finding evidence for a potential contribution of miRNAs to ACM pathogenesis or phenotype maintenance. Besides known pathways, we identified also deregulation of genes encoding ephrin receptors and ephrins, thus suggesting a potential involvement of Eph-ephrin signaling in CStCs from ACM hearts.
2018-06-27 | GSE95120 | GEO
Project description:Introduction: We have reported that iPSC-cardiac myocytes from patients with arrhythmogenic cardiomyopathy (ACM) mount an intense innate immune response under basal conditions in vitro. In addition, blocking innate immune signaling via NFκB prevents disease in a mouse model of ACM (Dsg2mut/mut mice). Here, we defined the relative pathogenic roles of immune signaling in cardiac myocytes vs. infiltrating inflammatory cells in Dsg2mut/mut mice. Methods: To define the role of immune signaling in cardiac myocytes, we bred Dsg2mut/mut mice with mice with cardiac myocyte-specific expression of a dominant-negative form of IκBα (DN-IκBα), which prevents nuclear translocation and, thereby, activation of NFκB signaling only in cardiac myocytes. To define the role of inflammatory cells in ACM, we focused on cells expressing C-C motif chemokine receptor-2 (CCR2+ cells), known to mediate adverse cardiac remodeling and fibrosis. We bred Dsg2mut/mut mice with germline deletion of Ccr2 mice (Ccr2-/- mice). We compared phenotypes in Dsg2mut/mut mice with double-mutant Dsg2mut/mut X DN-IκB and Dsg2mut/mut X Ccr2-/- lines. Results: Dsg2mut/mut mice develop marked myocardial fibrosis, reduced LV ejection fraction (EF) and many PVCs. These disease features were all normalized in Dsg2mut/mut X DN-IκB mice. Hearts of Dsg2mut/mut and Dsg2mut/mut X DN-IκB mice contained equal numbers of CD68+ macrophages, but Dsg2mut/mut hearts had many more CCR2+ cells. Cardiac myocyte expression of Tlr4 which activates NFκB, was increased in Dsg2mut/mut mice but not in Dsg2mut/mut X Ccr2-/- mice. Dsg2mut/mut X Ccr2-/- mice showed greatly reduced myocardial fibrosis and PVCs but LV EF was markedly depressed. This suggested that contractile dysfunction in ACM is due not only to loss of muscle but to immune signaling in viable cardiac myocytes as well. To test this hypothesis, we treated Dsg2mut/mut and Dsg2mut/mut X Ccr2-/- mice with the NFκB inhibitor Bay 11-7082. Before treatment, LV EFs were significantly reduced in both groups. Untreated Dsg2mut/mut mice had ongoing deterioration of LV function, whereas treated Dsg2mut/mut mice showed no further disease progression and actually had some improvement in contractile function. However, LV function in treated Dsg2mut/mut X Ccr2-/- mice was virtually normalized. Conclusions: NFκB signaling in cardiac myocytes drives myocardial injury, LV dysfunction and arrhythmias in Dsg2mut/mut mice. It also mobilizes CCR2+ cells to the heart, where they promote myocardial injury and arrhythmias. CCR2+ cells alter gene expression in cardiac myocytes. LV dysfunction in Dsg2mut/mut mice is caused not only by muscle loss but also by negative inotropic effects of inflammation mediated by NFκB in viable cardiac myocytes. These results have obvious implications for ACM patients and suggest that anti-inflammatory therapy may be beneficial even in patients with established disease.
2024-02-28 | GSE228048 | GEO
Project description:Arrhythmogenic cardiomyopathy (ACM) is an inherited progressive cardiomyopathy. The pathophysiological events are well understood, yet the underlying molecular mechanisms remain undefined. Here we use patient originated hiPSC-derived cardiomyocytes bearing a pathogenic PKP2 mutation (PKP2 c.2013delC/WT), a corresponding knock-in mouse model carrying the equivalent murine mutation (Pkp2 c.1755delA/WT), and human explanted ACM hearts, to identify disease driving mechanisms. Pkp2 c.1755delA/WT mice over time displayed signs of ACM as observed by cardiac dysfunction and pathological remodeling. At a molecular level these mice showed a reduction in desmosomal and adherens junction proteins as well as disarray of the intercalated discs in areas of active fibrotic remodeling. These findings were validated in the mutant hiPSC-derived cardiomyocytes as well as human explanted ACM hearts, indicating both the conservation and relevance of protein degradation in the pathogenesis of the disease. Led by proteomics data, we demonstrated that the ubiquitin-proteasome system was responsible for the observed desmosomal protein degradation. These findings show the importance of appropriate disease modeling and provide means for therapeutic intervention for the prevention of ACM disease progression.
2023-03-23 | GSE160289 | GEO
Project description:The cWNT pathway has been implicated in the pathogenesis of arrhythmogenic cardiomyopathy (ACM), including in cardiac dysfunction, apoptosis, and fibro-adipogenesis, the latter being the histological hallmark of ACM. The study was designed to determine effects of genetic activation or suppression of cWNT in a mouse model of arrhythmogenic cardiomyopathy. The data show that activation of the cWNT in ACM deleterious whereas it suppression is benefiial.
2022-02-02 | GSE180972 | GEO
Project description:Single cell RNA transcriptome analysis of Epicardial Derived Cells in the Desmoplakin haplo-insufficient Arrhythmogenic Cardiomyopathy mouse
| PRJNA634559 | ENA
Project description:Human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) are commonly used to model arrhythmogenic cardiomyopathy (ACM), a heritable cardiac disease characterized by severe ventricular arrhythmias, fibrofatty myocardial replacement and progressive ventricular dysfunction. Although ACM is inherited as an autosomal dominant disease, incomplete penetrance and variable expressivity are extremely common, resulting in different clinical manifestations. Here, we propose hiPSC-CMs as a powerful in vitro model to study incomplete penetrance in ACM. Six hiPSC lines were generated from blood samples of three ACM patients carrying a heterozygous deletion of exon 4 in the PKP2 gene, two asymptomatic (ASY) carriers of the same mutation and one healthy control (CTR), all belonging to the same family. Whole exome sequencing was performed in all family members and hiPSC-CMs were examined by ddPCR, western blot, Wes™ immunoassay system, patch clamp, immunofluorescence and RNASeq. Our results show molecular and functional differences between ACM and ASY hiPSC_x0002_CMs, including a higher amount of mutated PKP2 mRNA, a lower expression of the connexin-43 protein, a lower overall density of sodium current, a higher intracellular lipid accumulation and sarcomere disorganization in ACM compared to ASY hiPSC_x0002_CMs. Differentially expressed genes were also found, supporting a predisposition for a fatty phenotype in ACM hiPSC-CMs. These data indicate that hiPSC-CMs are a suitable model to study incomplete penetrance in ACM.
2023-07-14 | GSE222793 | GEO
Project description:Different cell types individually contribute to set the Arrhythmogenic Cardiomyopathy (ACM) phenotype with either functional abnormalities (cardiomyocytes; CM) or fibro-fatty substitution (cardiac mesenchymal stromal cells; cMSC). The relative contribution of the CM and cMSC derangements to determine disease evolution and electrical instability is still poorly understood. Here we showed that a patient-specific multicellular cardiac system, which models the functional interaction between CM and cMSC, provides insight into the relative contribution of different cell types to ACM phenotypes.
2024-11-05 | GSE249301 | GEO
Project description:Arrhythmogenic cardiomyopathy (ACM) is an inherited progressive cardiomyopathy. The pathophysiological events are well understood, yet the underlying molecular mechanisms remain undefined. Here we use patient originated hiPSC-derived cardiomyocytes bearing a pathogenic PKP2 mutation (PKP2 c.2013delC/WT), a corresponding knock-in mouse model carrying the equivalent murine mutation (Pkp2 c.1755delA/WT), and human explanted ACM hearts, to identify disease driving mechanisms. Pkp2 c.1755delA/WT mice over time displayed signs of ACM as observed by cardiac dysfunction and pathological remodeling. At a molecular level these mice showed a reduction in desmosomal and adherens junction proteins as well as disarray of the intercalated discs in areas of active fibrotic remodeling. These findings were validated in the mutant hiPSC-derived cardiomyocytes as well as human explanted ACM hearts, indicating both the conservation and relevance of protein degradation in the pathogenesis of the disease. Led by proteomics data, we demonstrated that the ubiquitin-proteasome system was responsible for the observed desmosomal protein degradation. These findings show the importance of appropriate disease modeling and provide means for therapeutic intervention for the prevention of ACM disease progression.
2023-03-23 | GSE199925 | GEO