Publication: 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
Authors
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.
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Publisher
Oxford University Press [University Publisher]
European Society of Cardiology [Society Publisher]
European Society of Cardiology [Society Publisher]
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DOI
https://doi.org/10.1093/cvr/cvab197
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info:eu-repo/semantics/article
Description
©2022. This document is the Published 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
Abstract
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.
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Citation
Cardiovascular Research 118(6) 2022: 1466-1478
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