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Single Nucleus RNA sequencing Identifies PLXNA4 Upregulation in End Stage Arrhythmogenic Right Ventricular Cardiomyopathy [RNA-seq]

ABSTRACT: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare genetic form of heart disease often caused by mutations in desmosomal proteins. We carried out single-nucleus RNA sequencing (snRNA-seq) on 11 non-failing and 8 ARVC patient right ventricular samples and transcriptionally profiled 139,347 nuclei. We identified over 4,400 differentially expressed protein coding genes between non-failing and ARVC samples across cell types. When compared to dilated, hypertrophic and ischemic cardiomyopathy, we found that end stage ARVC is transcriptionally similar to other forms of end stage heart failure. Despite broad transcriptional similarities, we identified seven cardiomyocyte genes and six fibroblast genes that were uniquely dysregulated in ARVC and validated PLXNA4 as a gene with uniquely increased expression in cardiomyocytes in ARVC compared to other cardiomyopathies. Overexpression of PLXNA4 in hiPSC-derived ventricular cardiomyocytes induced immune response gene expression, suppressed calcium signaling, and altered cardiomyocyte electrophysiology, suggesting PLXNA4 may contribute to these pathways in ARVC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE335263 | GEO | 2026/08/14

REPOSITORIES: GEO

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Single Nucleus RNA sequencing Identifies PLXNA4 Upregulation in End Stage Arrhythmogenic Right Ventricular Cardiomyopathy

Project description:Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare genetic form of heart disease often caused by mutations in desmosomal proteins. We carried out single-nucleus RNA sequencing (snRNA-seq) on 11 non-failing and 8 ARVC patient right ventricular samples and transcriptionally profiled 139,347 nuclei. We identified over 4,400 differentially expressed protein coding genes between non-failing and ARVC samples across cell types. When compared to dilated, hypertrophic and ischemic cardiomyopathy, we found that end stage ARVC is transcriptionally similar to other forms of end stage heart failure. Despite broad transcriptional similarities, we identified seven cardiomyocyte genes and six fibroblast genes that were uniquely dysregulated in ARVC and validated PLXNA4 as a gene with uniquely increased expression in cardiomyocytes in ARVC compared to other cardiomyopathies. Overexpression of PLXNA4 in hiPSC-derived ventricular cardiomyocytes induced immune response gene expression, suppressed calcium signaling, and altered cardiomyocyte electrophysiology, suggesting PLXNA4 may contribute to these pathways in ARVC.

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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

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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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Project description:Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a familial cardiac disease associated with ventricular arrhythmias and an increased risk of sudden cardiac death. Currently, there are no approved treatments that address the underlying genetic cause of this disease, representing a significant unmet need. Mutations in Plakophilin-2 (PKP2), encoding a desmosomal protein, account for approximately 40% of ARVC cases and result in reduced gene expression. Methods: Our goal is to examine the feasibility and the efficacy of adeno-associated virus 9 (AAV9)-mediated restoration of PKP2 expression in a cardiac specific knock-out mouse model of Pkp2. Results: We show that a single dose of AAV9:PKP2 gene delivery prevents disease development before the onset of cardiomyopathy and attenuates disease progression after overt cardiomyopathy. Restoration of PKP2 expression leads to a significant extension of lifespan by restoring cellular structures of desmosomes and gap junctions, preventing or halting decline in left ventricular ejection fraction, preventing or reversing dilation of the right ventricle, ameliorating ventricular arrhythmia event frequency and severity, and preventing adverse fibrotic remodeling. RNA sequencing analyses show that restoration of PKP2 expression leads to highly coordinated and durable correction of PKP2-associated transcriptional networks beyond desmosomes, revealing a broad spectrum of biological perturbances behind ARVC disease etiology. Conclusions: We identify fundamental mechanisms of PKP2-associated ARVC beyond disruption of desmosome function. The observed PKP2 dose-function relationship indicates that cardiac-selective AAV9:PKP2 gene therapy may be a promising therapeutic approach to treat ARVC patients with PKP2 mutations.

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Project description:Pericardial fluid is enriched by biologically active molecules of cardiovascular origin including microRNAs. Investigation of the disease-specific extracellular microRNAs could shed light on the molecular processes underlying disease development. Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart disease characterized by life-threatening arrhythmias and progressive heart failure development. The current data about the association between microRNAs and ARVC development are limited. We performed small RNA sequence analysis of microRNAs of pericardial fluid samples obtained during transcutaneous epicardial access for ventricular tachycardia (VT) ablation of six patients with definite ARVC and three post-infarction VT patients. Disease-associated microRNAs of pericardial fluid were identified. Enrichment analysis of differentially expressed microRNAs revealed their close linkage to cardiac diseases.

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Project description:Arrhythmogenic cardiomyopathy (AC) is an inherited cardiomyopathy characterized by fibrofatty replacement predominantly involved in right ventricle and clinically by ventricular arrhythmias.In this study, we set out to characterize the cardiac novel long-noncoding RNAs using deep RNA sequencing data from human heart tissues. Particularly, we identified AC specific novel lncRNAs that contribute to AC pathophysiology by comparing the lncRNAs transcripts of nine AC explanted hearts (RV), five non-diseased donor hearts (RV), four non-AC failing hearts (dilated cardiomyopathy, RV). To dissect the roles of novel lncRNAs in ARVC from LV, we also include six non-diseased donor hearts (LV) and six ARVC explanted hearts (LV) in the analysis. In the identified novel AC lncRNAs, a large part of them are derived from enhancer regions and acting as cis- elements to potentially regulate lipogenesis or lipid metabolism related genes. Finally, we validated several of these AC specific novel lncRNAs and their potential targets in independent patient samples. Collectively, we identified high-confidence AC specific novel lncRNAs from human samples and suggest their potential roles as cis- elements in AC pathology. Further study of these novel AC lncRNAs could provide new opportunities for diagnosis and therapeutic intervention.

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