期刊
CARDIOVASCULAR RESEARCH
卷 118, 期 6, 页码 1466-1478出版社
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvab197
关键词
Cardiomyopathy; Hippo pathway; WNT pathway; TP53; RNA-sequencing; Gene expression
资金
- Instituto de Salud Carlos III
- FEDER Union Europea
- Una forma de hacer Europa [PI18/01582]
- La Fe Biobank [PT17/0015/0043]
- National Institutes of Health (NIH), National Heart, Lung and Blood Institute [NHLBI: 1R01HL132401, R01HL151737]
- NIH [S10 OD018135]
- Leducq Foundation [14 CVD 03]
- NIA [R21AG060413-01]
- Ewing Halsell Foundation
- George and Mary Josephine Hamman Foundation
- Greater Houston Community Foundation
In patients with ACM caused by specific gene mutations without overt heart failure, altered apical junction structures are associated with activation of EP300-TP53 and suppression of the Hippo/cWNT pathways. This suggests a role for altered mechanotransduction in the pathogenesis of ACM.
Aims Arrhythmogenic cardiomyopathy (ACM) is a primary myocardial disease that typically manifests with cardiac arrhythmias, progressive heart failure, and sudden cardiac death (SCD). ACM is mainly caused by mutations in genes 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 similar to 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. Conclusion Altered apical junction structures are associated with activation of the EP300-TP53 and suppression of the Hippo/cWNT pathways in human ACM caused by defined mutations in the absence of an overt heart failure. The findings implicate altered mechanotransduction in the pathogenesis of ACM.
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