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Microarray analysis of miRNAs in atrial tissue from chronic AF patients

ABSTRACT: OBJECTIVES: This study aims to define a microRNA signature in chronic AF (CAF) and to unravel key target genes contributing to the atrial remodelling. METHODS: Total RNA from atrial biopsies of 2 sinus rhythm (SR) and 4 CAF patients was analyzed by microRNA(miR)-array. Expression of most deregulated miRs and their actions on specific targets were confirmed by qRT-PCR in human and ovine samples and validated in HL-1 cells and myocytes isolated from CAF patients. After bioinformatics prediction of targets and signaling, and through lentiviral miR-transduction or mimics-miR transfection of HL-1 cells, effects on main predicted regulatory pathways were analyzed. RESULTS: 38 microRNAs showed significant changes in expression in CAF atrial samples (>2-fold) and among them, miR-208a and miR-208b were confirmed to be significantly upregulated (>2 and >5-fold, respectively). Bioinformatics analysis predicted 70 pairs of CAF-altered mRNAs/miR-208a/b interactions. We confirmed that miR-208a and b directly targeted muscle cardiac gene program and canonical Wnt-signaling receptors and seemed to repress indirectly CX43. L-type Ca(2+) channel genes (CACNA1C and CACNB2) and sarcoplasmic reticulum-calcium pump SERCA2 were repressed by miR-208b at transcriptional, posttranscriptional and functional levels. CONCLUSION:In this work we report for the first time the role of miR-208b upregulation in the control of calcium balance in CAF.

ORGANISM(S): Homo sapiens

PROVIDER: GSE70887 | GEO | 2015/07/15

SECONDARY ACCESSION(S): PRJNA289857

REPOSITORIES: GEO

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Project description:Objective: To explore the protective effects of exercise-derived β-aminoisobutyric (BAIBA) on apoptosis and energy metabolism in rats with heart failure. Methods: A rat model of heart failure after myocardial infarction (MI) was started by ligating the left anterior descending branch of the coronary artery, the anterior descending branch of the rats in the SHAM group was only threaded and not ligated. Exercise intervention was given to rats with heart failure. The possible mechanisms by which exercise affected cardiac remodeling after MI were investigated using color ultrasound, HE, Masson, and TUNEL staining, and the detection of apoptosis-associated factors in cardiac tissue. High-throughput sequencing and mass spectrometry were used to measure the production of BAIBA and to explore its protective effects and molecular mechanisms. An in vitro model of apoptosis was created by the application of H2O2 to induce mitochondrial dysfunction. This was then transfected with miR-208b analogue and miR-208b-inhibitor. Apoptosis-related proteins were detected by Western blotting (WB), and ATP production was also assessed. After intervention with BAIBA and compound C, assessments were made of apoptosis, mitochondrial function, lipid uptake, utilization of related proteins, ATP changes, alterations in membrane potential (δψm), and changes in reactive oxygen species (ROS). Results: Compared with the control heart failure (HF) group, exercise improved the function of mitochondria, reversed the expression of apoptosis-related proteins, and increased ATP production. In both the normal and heart failure groups, exercise significantly increased the production of BAIBA. It was shown that BAIBA played a similar role to exercise in ameliorating heart failure. Transcriptome analysis confirmed that the expression of miR-208b was increased after BAIBA intervention, and transfection with miR-208b analogue increased both the expression of apoptosis-related proteins and energy metabolism in H9C2 cells induced by H2O2. Combined analysis of the transcriptome and metabolome identified AMPK as a target for BAIBA to improve metabolic stress. Cell experiments further confirmed that BAIBA increased AMPK phosphorylation and had a protective effect on downstream fatty acid uptake, oxidative efficiency, and mitochondrial function, which could be counteracted by the AMPK inhibitor compound C. Conclusion: Exercise-induced BAIBA can reduce the metabolic stress and apoptosis induced by mitochondrial dysfunction through the miR-208b/AMPK pathway.

Project description:Atrial fibrillation (AF) is a progressive arrhythmia for which current therapy is inadequate. During AF, rapid stimulation causes atrial remodeling that promotes further AF. The cellular signals that trigger this process remain poorly understood, however, and elucidation of these factors would likely identify new therapeutic targets. We have previously shown that immortalized mouse atrial (HL-1) myocytes subjected to 24 hr of rapid stimulation in culture undergo remodeling similar to that seen in animal models of atrial tachycardia (AT) and human AF. This preparation is devoid of confounding in vivo variables that can modulate gene expression (e.g., hemodynamics). Therefore, we investigated the transcriptional profile associated with early atrial cell remodeling. RNA was harvested from HL-1 cells cultured for 24 hr in the absence and presence of rapid stimulation and subjected to microarray analysis. Data were normalized using Robust Multichip Analysis (RMA), and genes exhibiting significant differential expression were identified using the Significance Analysis of Microarrays (SAM) method. Using this approach, 919 genes were identified that were significantly altered with rapid stimulation (763 up-regulated and 156 down-regulated). For many individual transcripts, changes typical of AF/AT were observed, with marked up-regulation of genes encoding BNP and ANP precursors, heat shock proteins, and MAP kinases, while novel signaling pathways and molecules were also identified. Both stress and survival response were evident, as well as up-regulation of multiple transcription factors. Genes were also functionally classified based on cellular component, biologic process, and molecular function using the Gene Ontology database to permit direct comparison of our data with other gene sets regulated in human AF and experimental AT. For broad categories of genes grouped by functional classification, there was striking conservation between rapidly stimulated HL-1 cells and AF/AT. Results were confirmed using real-time quantitative RT-PCR on 13 genes selected by physiological relevance in AF/AT and regulation in the microarray analysis (up, down, and nonregulated). Rapidly-stimulated atrial myocytes provide a complementary experimental paradigm to explore the initial cellular signals in AT remodeling to identify novel targets in the treatment of AF. Experiment Overall Design: HL-1 cell expression profile in vitro with and without rapid electric stimulation

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Microarray analysis of miRNAs in atrial tissue from chronic AF patients

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