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https://doi.org/10.1093/cvr/cvab197
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Título: | The EP300/TP53 pathway, a suppressor of the Hippo and canonical WNT pathways, is activated in human hearts with arrhythmogenic cardiomyopathy in the absence of overt heart failure |
Fecha de publicación: | 14-jun-2021 |
Editorial: | Oxford University Press [University Publisher] European Society of Cardiology [Society Publisher] |
Cita bibliográfica: | Cardiovascular Research; 118(6) 2022: 1466-1478 |
ISSN: | Print: 0008-6363 Electronic: 1755-3245 |
Palabras clave: | Cardiomyopathy Hippo pathway WNT pathway TP53 RNA-sequencing Gene expression |
Resumen: | Aims Arrhythmogenic cardiomyopathy (ACM) is a primary myocardial disease that typically manifests with cardiacarrhythmias, progressive heart failure, and sudden cardiac death (SCD). ACM is mainly caused by mutations ingenes encoding desmosome proteins. Desmosomes are cell–cell adhesion structures and hubs for mechanosensing and mechanotransduction. The objective was to identify the dysregulated molecular and biological pathways in human ACM in the absence of overt heart failure. Methods and results Transcriptomes in the right ventricular endomyocardial biopsy samples from three independent individuals carrying truncating mutations in the DSP gene and five control samples were analysed by RNA-Seq (discovery group). These cases presented with cardiac arrhythmias and had a normal right ventricular function. The RNA-Seq analysis identified 5000 differentially expressed genes (DEGs), which predicted suppression of the Hippo and canonical WNT pathways, among others. Dysregulated genes and pathways, identified by RNA-Seq, were tested for validation in the right and left ventricular tissues from five independent autopsy-confirmed ACM cases with defined mutations (validation group), who were victims of SCD and had no history of heart failure. Protein levels and nuclear localization of the cWNT and Hippo pathway transcriptional regulators were reduced in the right and left ventricular validation samples. In contrast, levels of acetyltransferase EP300, known to suppress the Hippo and canonical WNT pathways, were increased and its bona fide target TP53 was acetylated. RNA-Seq data identified apical junction, reflective of cell–cell attachment, as the most disrupted biological pathway, which were corroborated by disrupted desmosomes and intermediate filament structures. Moreover, the DEGs also predicted dysregulation of over a dozen canonical signal transduction pathways, including the Tec kinase and integrin signalling pathways. The changes were associated with increased apoptosis and fibro-adipogenesis in the ACM hearts. |
Autor/es principal/es: | Rouhi, Leila Fan, Siyang Cheedipudi, Sirisha M. Braza Boils, Aitana Sabater Molina, María Yao, Yan Robertson, Matthew J. Coarfa, Cristian Gimeno, Juan Ramón Molina, Pilar Gurha, Priyatansh Zorio, Esther Marian, Ali J. |
Facultad/Departamentos/Servicios: | Facultades, Departamentos, Servicios y Escuelas::Departamentos de la UMU::Ciencias Sociosanitarias |
URI: | http://hdl.handle.net/10201/139286 |
DOI: | https://doi.org/10.1093/cvr/cvab197 |
Tipo de documento: | info:eu-repo/semantics/article |
Número páginas / Extensión: | 13 |
Derechos: | info:eu-repo/semantics/openAccess Attribution-NonCommercial-NoDerivatives 4.0 Internacional |
Descripción: | ©2022. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/ This document is the Accepted, version of a Published Work that appeared in final form in Cardiovascular Research. To access the final edited and published work see https://doi.org/10.1093/cvr/cvab197 |
Aparece en las colecciones: | Artículos: Ciencias Sociosanitarias |
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