Characterizing the global changes in miRNA expression in human atrial appendages with persistent atrial fibrillation.
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE68475 | GEO | 2017/04/25
SECONDARY ACCESSION(S): PRJNA283137
REPOSITORIES: GEO
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Project description:Atrial fibrillation (AF) is often a progressive cardiac arrhythmia that increases the risk of hospitalization and adverse cardiovascular events. There is a clear demand for more inclusive and large-scale approaches to understand the molecular drivers responsible for AF, as well as the fundamental mechanisms governing the transition from paroxysmal to persistent and permanent forms. We aimed to create a molecular map of AF and find the distinct genetic programs underlying cell type-specific atrial remodeling and AF progression. We used a sheep model of long-standing, tachypacing-induced AF, sampled right and left atrial tissue and isolated cardiomyocytes from control, intermediate (transition) and late time points during AF progression, and performed transcriptomic and proteome profiling. We have merged all these layers of information into a meaningful 3-component space in which we explored the genes and proteins detected and their common patterns of expression. Our data-driven analysis points at extracellular matrix remodeling, inflammation, ion channel, myofibril structure, mitochondrial complexes and chromatin remodeling as hallmarks of AF progression. Most important, we prove that these changes occur at early transitional stages of the disease, but not at later stages, and that the left atrium undergoes significantly more profound changes than the right atrium in its expression program. The pattern of dynamic changes in gene and protein expression correspond closely with the electrical and structural remodeling demonstrated previously in the sheep and in humans. The results provide novel insight into the dynamics of gene and protein expression changes that underlie AF-induced atrial remodeling and that make the arrhythmia become more stable and long lasting.
2020-09-30 | GSE138255 | GEO
Project description:Atrial fibrillation (AF) is the most frequent persistent arrhythmia, and many genes have been reported as a causal gene candidate for AF. However, most transcriptome analyses of AF have limited to the atrial samples and have not evaluated by multiple cardiac regions. In this study, we analyzed the expression levels of protein-coding and long noncoding RNAs (lncRNAs) in six different cardiac regions by RNA-seq. Surprisingly, the most changed region in gene expression by the presence of AF was the pulmonary vein (PV), not the atria. Upon analysis of these significant genes, the ion channel-related gene set was significantly enriched. In addition, cancer-related lncRNAs was up-regulated in PV in AF. A Co-expression network analysis could detect the functional gene clusters. In particular, the functional coupling between the lncRNA FOXCUT and transcription factor FOXC1 are known to be involved in process of the epithelial-mesenchymal transition in cancer tissues. Thus, they may also play an aggravating role in the pathogenesis of AF. In the least, this study suggests that (1) RNA alteration is most intense in PVs and (2) post-acquired gene regulation, such as the FOXCUT-FOXC1 axis, may contribute to the progression of AF.
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Project description:Objectives: We studied the signal transduction of atrial structural remodelling that contributes to the pathogenesis of atrial fibrillation (AF). Backround: Fibrosis is a hallmark of arrhythmogenic structural remodelling but the underlying molecular mechanisms are incompletely understood. Methods: We performed transcriptional profiling of left atrial myocardium (LA) from patients with AF and sinus rhythm (SR) and applied cultured primary cardiac cells and transgenic mice with overexpression of constitutively active V12Rac1 (RacET) who develop AF at old age to characterize mediators of the signal transduction of atrial remodeling. Results: LA from patients with AF showed a marked upregulation of connective tissue growth factor (CTGF) expression compared SR patients. This was associated with increased fibrosis, NADPH-oxidase-, Rac1- and RhoA activity, upregulation of N-cadherin and connexin 43 (Cx43) expression and increased angiotensin II tissue concentration. In neonatal rat cardiac myocytes and -fibroblasts, a specific small molecule inhibitor of Rac1 or simvastatin completely prevented the angiotensin II induced upregulation of CTGF, Cx43 and N-cadherin expression. Transfection with small-inhibiting CTGF RNA blocked Cx43 and N-cadherin expression. RacET mice showed upregulation of CTGF, Cx43 and N-cadherin protein expression. Inhibition of Rac1 by oral statin treatment prevented these effects, identifying Rac1 as a key regulator of CTGF in vivo. Conclusion: The data identify CTGF as an important mediator of atrial structural remodelling during AF. Angiotensin II activates CTGF via activation of Rac1 and NADPH oxidase, leading to upregulation of Cx43, N-cadherin and interstitial fibrosis and therefore contributing to the signal transduction of atrial structural remodelling. Array design study consists of 5 Atrial Fibrillation patients and matched 5 samples of patients in sinus rhythm (controls).
2010-02-21 | E-GEOD-14975 | biostudies-arrayexpress