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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

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dc.contributor.authorRouhi, Leila
dc.contributor.authorFan, Siyang
dc.contributor.authorCheedipudi, Sirisha M.
dc.contributor.authorBraza Boils, Aitana
dc.contributor.authorYao, Yan
dc.contributor.authorRobertson, Matthew J.
dc.contributor.authorCoarfa, Cristian
dc.contributor.authorGimeno, Juan Ramón
dc.contributor.authorMolina, Pilar
dc.contributor.authorGurha, Priyatansh
dc.contributor.authorZorio, Esther
dc.contributor.authorMarian, Ali J.
dc.contributor.authorSabater Molina, María
dc.contributor.departmentCiencias Sociosanitarias
dc.date.accessioned2024-02-12T12:05:21Z
dc.date.available2024-02-12T12:05:21Z
dc.date.issued2021-06-14
dc.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
dc.description.abstractAims 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.es
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dc.identifier.citationCardiovascular Research 118(6) 2022: 1466-1478
dc.identifier.doihttps://doi.org/10.1093/cvr/cvab197
dc.identifier.issnPrint: 0008-6363
dc.identifier.issnElectronic: 1755-3245
dc.identifier.urihttp://hdl.handle.net/10201/139286
dc.languageenges
dc.publisherOxford University Press [University Publisher]
dc.publisherEuropean Society of Cardiology [Society Publisher]
dc.relationThe work was in part supported by grants from the Instituto de Salud Carlos III and FEDER Union Europea, Una forma de hacer Europa (PI18/01231 and PI18/01582) and (PI18/01231); FEDER Union Europea, Una forma de hacer Europa (PI18/01582) and La Fe Biobank (PT17/0015/0043). Memorial Nacho Barbera´. National Institutes of Health (NIH), National Heart, Lung and Blood Institute (NHLBI: 1R01HL132401 and R01HL151737). NIH (S10 OD018135). Leducq Foundation (14 CVD 03). NIA (R21AG060413-01). The Ewing Halsell Foundation, George and Mary Josephine Hamman Foundation, and TexGen Fund from Greater Houston Community Foundation.es
dc.rights.accessRightsinfo:eu-repo/semantics/restrictedAccess
dc.subjectCardiomyopathy
dc.subjectHippo pathway
dc.subjectWNT pathway
dc.subjectTP53
dc.subjectRNA-sequencing
dc.subjectGene expression
dc.titleThe 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 failurees
dc.typeinfo:eu-repo/semantics/articlees
dspace.entity.typePublicationes
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relation.isAuthorOfPublication.latestForDiscoveryf4a8b11b-9980-45e4-9d87-c430bde8beb2
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