Mechanisms of Innate Immune Injury in Arrhythmogenic Cardiomyopathy
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ABSTRACT:
PROVIDER: PRJNA947929 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23950039_1.fastq.gz | Fastqsanger.gz | |||
| SRR23950039_2.fastq.gz | Fastqsanger.gz | |||
| SRR23950040_1.fastq.gz | Fastqsanger.gz | |||
| SRR23950040_2.fastq.gz | Fastqsanger.gz | |||
| SRR23950041_1.fastq.gz | Fastqsanger.gz |
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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 is an inherited entity characterized by irregular cell-cell adhesion, cardiomyocyte death, fibro-fatty replacement of ventricular myocytes, leading to malignant ventricular arrythmias, contractile dysfunction and sudden cardiac death. Pathogenic variants in genes that encode desmosome are the predominant cause of arrhythmogenic cardiomyopathy. Moreover, signalling pathways such as Wnt/ß-catenin and transforming growth factor-β have been involved in the disease progression. However, still little is known about the molecular pathophysiological mechanisms that underlie arrhythmogenic cardiomyopathy pathogenesis. We used mRNA and small RNA sequencing to analyse the transcriptome of health and arrhythmogenic cardiomyopathy autopsied human hearts. Our results showed 697 differentially expressed genes, and eight differentially expressed miRNAs. Functional enrichment revealed mitochondrial respiratory-related pathways, impaired response to oxidative stress, apoptotic signalling pathway, inflammatory response-related and extracellular matrix response pathways. Furthermore, analysis of miRNA-mRNA interactome identified eleven negatively correlated miRNA-target pairs for arrhythmogenic cardiomyopathy. Our finding revealed novel arrhythmogenic cardiomyopathy-related miRNAs with important regulatory function in disease pathogenesis highlighting their value as potential key targets for therapeutic approaches.
2024-09-30 | GSE273295 | GEO
Project description:Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy primarily of the right ventricle characterized through fibrofatty replacement of cardiomyocytes. The genetic etiology in ARVC patients is most commonly caused by dominant inheritance and high genetic heterogeneity. Though histological examinations of ARVC affected human myocardium reveals fibrolipomatous replacement, the molecular mechanisms leading to loss of cardiomyocytes are largely unknown. We therefore analyzed the transcriptomes of 6 ARVC specimen derived from heart transplantation candidates and compared our findings to 6 non-failing donor hearts (NF) which could not be transplanted for technical reasons. In addition, we compared our findings to 7 hearts from patients with idiopathic dilated cardiomyopathy. From each heart left (LV) and right ventricular (RV) myocardial samples were analyzed by Affymetrix HG-U133 Plus 2.0 arrays, adding up to six sample groups. Unsupervised cluster analyses of the six sample groups revealed a clear separation of NF and cardiomyopathy samples. However, in contrast to the other samples, unsupervised cluster analyses revealed no distinct expression pattern in LV and RV samples from ARVC-hearts. We further identified differentially expressed transcripts using t-tests and found transcripts separating diseased and NF ventricular myocardium. Of note, in failing myocardium only about 15-16% of the genes are commonly regulated compared to NF samples. In addition both cardiomyopathies are clearly distinct on the transcriptome level. Comparison of the expression patterns between the failing RV and LV using a paired t-test revealed a lack of major differences between LV and RV gene expression in ARVC hearts. Microarrays were used to elucidate the differences between non-failing control hearts and those, suffering from arrhythmogenic right ventricular cardiomyopathy (ARVC).
2011-11-30 | E-GEOD-29819 | biostudies-arrayexpress
Project description:Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is an inherited cardiac disease characterized by fibro-fatty replacement of the myocardium that causes heart failure and sudden cardiac death. The most aggressive subtype of ARVC is ARVC type 5 (ARVC5), caused by a p.S358L mutation in TMEM43. The function and localization of TMEM43 and the mechanism by which the p.S358L mutation causes the disease, are unknown.
2019-07-12 | GSE101301 | 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:We performed bulk cell RNA sequencing (RNAseq) on epicardial cells generated from human induced pluripotent stem cells (hiPSCs) of an arrhythmogenic cardiomyopathy patient and their PKP2 reverted isogenic control. The goal of this experiment was to compare the transcriptomes of diseased and healthy cells.
2021-06-20 | GSE152669 | GEO
Project description:We performed single cell RNA sequencing (scRNAseq) on epicardial cells generated from human induced pluripotent stem cells (hiPSCs) of an arrhythmogenic cardiomyopathy patient and their PKP2 reverted isogenic control. The goal of this experiment was to analyze the process of epicardial to fibro-fatty celluar differentiation in diseased cells and compare the cellular transcirptomes of diseased and healthy cells.
2021-06-20 | GSE149331 | 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:Epicardial Differentiation Drives Fibro-fatty Remodeling in Arrhythmogenic Cardiomyopathy
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Project description:Desmosomal protein degradation as underlying causes of arrhythmogenic cardiomyopathy
| PRJNA672884 | ENA