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Transcriptomic characterization of a human in vitro model of arrhythmogenic cardiomyopathy under topological and mechanical stimuli

ABSTRACT: Transcriptomic characterization of a human in vitro model of arrhythmogenic cardiomyopathy under topological and mechanical stimuli

PROVIDER: PRJNA475574 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR7290430.fastq.gz	Fastqsanger.gz
	SRR7290431.fastq.gz	Fastqsanger.gz
	SRR7290432.fastq.gz	Fastqsanger.gz
	SRR7290433.fastq.gz	Fastqsanger.gz
	SRR7290426.fastq.gz	Fastqsanger.gz

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Transcriptomic characterization of a human in vitro model of arrhythmogenic cardiomyopathy under topological and mechanical stimuli

Project description:Cell junctions play an important role in coordinating intercellular communication and intracellular ultrastructures, with desmosomes representing the mechanical component of such intercellular connections. Mutations to desmosomal component proteins compromise both inter- and intracellular signalling and correlate with severe diseases like arrhythmogenic cardiomyopathy (AC), with pathological phenotypes in tissues subjected to intense mechanical stimuli (skin and heart). Here, we explore the consequences of dysfunctional desmosomes in one line of induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) derived from an AC patient with a homozygous pathogenic mutation in desmosomal component protein plakophilin-2 (PKP2). We specifically aim at investigating the response to mechanical stress in an AC-pathological setting. To this aim, we aligned hiPS-CMs on stretchable patterned substrates to mimic the cardiac functional syncytium and compared transcriptomic profiles of PKP2-mutated hiPS-CMs and healthy controls. AC-CMs display altered transcription towards a pro-fibrotic gene expression program, and concurrent dysregulation of gene sets closely associated with cell-to-cell connections. By integrating the culture substrate with a macroscopic stretching setup able to accurately apply cyclic uniaxial elongation, we show how response to mechanical loads in AC-CMs deviates from the canonical mechanical-stress response observed in healthy-CMs.

2018-12-22 | GSE115621 | GEO

Unravelling Role of miRNA-mRNA Interactome in Pathophysiology of Arrhythmogenic Cardiomyopathy [mRNA-seq]

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

Myocardial transcriptome analysis of human arrhythmogenic right ventricular cardiomyopathy (ARVC)

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

Pathophysiology and therapeutics of arrhythmogenic right ventricular cardiomyopathy 5

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.

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Genetic Activation and Suppression of the Canonical WNT Pathway in Cardiac Myocyte-Specific Dsp Deficient Mouse Model of Arrhythmogenic Cardiomyopathy

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

Epicardial Differentiation Drives Fibro-fatty Remodeling in Arrhythmogenic Cardiomyopathy [bulk RNA-seq]

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

Epicardial Differentiation Drives Fibro-fatty Remodeling in Arrhythmogenic Cardiomyopathy [scRNA-seq]

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

Mechanisms of Innate Immune Injury in Arrhythmogenic Cardiomyopathy

Project description:Mechanisms of Innate Immune Injury in Arrhythmogenic Cardiomyopathy

| PRJNA947929 | ENA

Innate immune activation modulates contractile and electrical dysfunction in engineered heart tissue models fordesmoplakin(DSP)cardiomyopathy.

Project description:Desmosomes are specialized cell-cell junctions critically important in the heart, where their disruption promotes arrhythmogenic cardiomyopathy (ACM). Individuals carrying truncating variants in the desmosomal gene desmoplakin (DSP) often show a prominent inflammatory component in the absence of known antigenic stimuli, termed “hot phase” arrythmia. To assess the role of innate immune activation in DSP-cardiomyopathy, we generated engineered heart tissues (EHTs) from two patients with heterozygous DSP truncation variants (DSPtv, p.E1597X and p.R1951X). We also generated EHTs with homozygous DSP deletion (DSP-/-) for modeling. DSP-/- EHTs revealed impaired force production and reduced conduction velocity compared to isogenic controls, features consistent with ACM. RNA sequencing and protein characterization demonstrated a dramatic increase in innate immune activation in DSP-/- EHTs. Similarly, patient-derived DSPtv EHTs show enhanced sensitivity to inflammatory stimuli seen as reduced contractility and greater cytokine release. Inhibition of NFκB signaling improved baseline force production and mechanical response to strain in DSPtv EHTs, indicating that anti-inflammatory modulation may improve mechanical function in DSP deficient hearts. Furthermore, genomic correction of p.R1951X using adenine base editing reduced inflammatory biomarkers in cultured EHTs. Taken together, these data identify that DSPtv promote innate immune activation, creating an arrhythmogenic substrate in the concealed phase of ACM.

2024-07-03 | GSE248187 | GEO

Expression analysis of Acacia koa in response to mechanical stimuli

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2015-12-14 | E-GEOD-73889 | biostudies-arrayexpress

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