Exploring Regulatory Mechanisms of Atrial Myocyte Hypertrophy of Mitral Regurgitation through Gene Expression Profiling Analysis: Role of NFAT in Cardiac Hypertrophy
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE63045 | GEO | 2016/11/07
SECONDARY ACCESSION(S): PRJNA266508
REPOSITORIES: GEO
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Project description:BackgroundLeft atrial enlargement in mitral regurgitation (MR) predicts a poor prognosis. The regulatory mechanisms of atrial myocyte hypertrophy of MR patients remain unknown.Methods and resultsThis study comprised 14 patients with MR, 7 patients with aortic valve disease (AVD), and 6 purchased samples from normal subjects (NC). We used microarrays, enrichment analysis and quantitative RT-PCR to study the gene expression profiles in the left atria. Microarray results showed that 112 genes were differentially up-regulated and 132 genes were differentially down-regulated in the left atria between MR patients and NC. Enrichment analysis of differentially expressed genes demonstrated that "NFAT in cardiac hypertrophy" pathway was not only one of the significant associated canonical pathways, but also the only one predicted with a non-zero score of 1.34 (i.e. activated) through Ingenuity Pathway Analysis molecule activity predictor. Ingenuity Pathway Analysis Global Molecular Network analysis exhibited that the highest score network also showed high association with cardiac related pathways and functions. Therefore, 5 NFAT associated genes (PPP3R1, PPP3CB, CAMK1, MEF2C, PLCE1) were studies for validation. The mRNA expressions of PPP3CB and MEF2C were significantly up-regulated, and CAMK1 and PPP3R1 were significantly down-regulated in MR patients compared to NC. Moreover, MR patients had significantly increased mRNA levels of PPP3CB, MEF2C and PLCE1 compared to AVD patients. The atrial myocyte size of MR patients significantly exceeded that of the AVD patients and NC.ConclusionsDifferentially expressed genes in the "NFAT in cardiac hypertrophy" pathway may play a critical role in the atrial myocyte hypertrophy of MR patients.
| S-EPMC5131988 | biostudies-literature
Project description:We conducted single-cell RNA sequencing analysis of mitral valve leaflets extracted from six patients, comprising three individuals with moderate-to-severe functional mitral regurgitation and three nondiseased mitral valve controls. Bioinformatics was used to identify the cell types, describe the cell functions, and investigate cellular developmental trajectories and interactions.
2024-12-27 | GSE241947 | GEO
Project description:Mitral valve leaflet response to ischemic mitral regurgitation: From gene expression to tissue remodeling
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Project description:Regulatory Mechanisms of Atrial Remodeling of Mitral Regurgitation Pigs
2015-02-01 | GSE43072 | GEO
Project description:Purpose: The goal of this study is to compare mRNA related cellular pathways associated with mitral regurgitation compared to Sham Methods: RNA was extracted from myocardial tissue at 2, 10, 20, 40 weeks after MR surgery (n=5 samples/time-point) and was subjected to unbiased RNA sequencing. Conclusions: RNA sequencing revealed an early activation of multiple cellular pathways.
2020-11-30 | GSE148559 | GEO
Project description:Regulatory Mechanisms of Atrial Remodeling of Mitral Regurgitation Pigs This study enrolled 6 pigs (age: 18 months) and divided into three groups: mitral regurgitation pigs (MR) (n = 2; 2 males sacrificed 12 months after surgery), MR pigs treated with valsartan (MRV) (n = 2; 2 males age-matched to MR sacrificed 12 months after surgery), and normal control pigs (NC) (n = 2; 2 males age-matched to MR pigs). Valsartan (3.43 mg/kg/day), a type I angiotensin II receptor blocker, was administered from one week before surgery and then daily after surgery in the MRV group. We sought to systemically elucidate critical differences in the alteration of RNA expression pattern between the atrial myocardium of pigs with and without MR, and between the atrial myocardium of MR pigs with and without valsartan using high-density oligonucleotide microarrays and functional network enrichment analysis.
2015-02-01 | E-GEOD-43072 | biostudies-arrayexpress
Project description:Rationale: Ischemic mitral regurgitation (IMR) is frequently observed following myocardial infarction (MI) and is associated with higher mortality and poor clinical prognosis if left untreated. Accumulating evidence suggests that mitral valve (MV) leaflets actively remodel post-MI, yet the cellular mechanisms underlying these responses and how this affects tissue function remain largely unknown. Objective: We sought to elucidate MV remodeling post-MI at the tissue, cellular, and transcriptomic levels. Methods and Results: The mechanical behavior of ovine MV leaflets pre-MI and 8 weeks post-MI reveal a significant decrease in radial direction extensibility, which essentially eliminated the mechanical anisotropy typically observed in healthy MVs. Quantitative histology and ultrastructural assessment by transmission electron microscopy revealed altered leaflet composition and architecture at 8 weeks post-MI. Assessment of the MV interstitial cell (MVIC) nuclear aspect ratio, a metric of cellular deformation, revealed that MVICs were on average rounder following MI. RNA sequencing (RNA-seq) indicated that YAP-induced genes were elevated at 4 weeks post-MI and genes related to extracellular matrix organization were some of the most downregulated in sheep with IMR compared to sheep without IMR at 4 weeks post-MI. Additionally, RNA-seq revealed the possible recruitment of immune cells in this remodeling process due to the drastic elevation of CXCL9 and CLEC10A. Conclusions: This multiscale assessment revealed significant mechanical and microstructural changes due to MI. RNA-seq provided a baseline for global gene expression changes in response to MI with and without IMR and suggests YAP-induced mechanotransduction, altered expression of ECM-related genes, and recruitment of immune cells as mechanisms contributing to altered MV biomechanics post-MI. Conclusions: This multiscale assessment revealed significant mechanical and microstructural changes due to MI. RNA-seq provided a baseline for global gene expression changes in response to MI with and without IMR and suggests YAP-induced mechanotransduction, altered expression of ECM-related genes, and recruitment of immune cells as mechanisms contributing to altered MV biomechanics post-MI.
2020-05-06 | GSE139921 | GEO
Project description:Background: Following myocardial infarction, mitral regurgitation (MR) is a common complication. Previous animal studies demonstrated the association of endothelial-to-mesenchymal transition (EndMT) with mitral valve (MV) remodeling. Nevertheless, little is known about how MV tissue responds to ischemic heart changes in humans. Methods: MVs were obtained by the Cardiothoracic Surgical Trials Network from 17 patients with ischemic mitral regurgitation (IMR). Echo-doppler imaging assessed MV function at time of resection. Cryosections of MVs were analyzed using a multi-faceted histology and immunofluorescence examination of cell populations. MVs were further analyzed using unbiased label-free proteomics. Echo-Doppler imaging, histo-cytometry measures and proteomic analysis were then integrated. Results: MVs from patients with greater MR exhibited proteomic changes associated with proteolysis-, inflammatory- and oxidative stress-related processes compared to MVs with less MR. Cryosections of MVs from patients with IMR displayed activated valvular interstitial cells (aVICs) and double positive CD31+ αSMA+ cells, a hallmark of EndMT. Univariable and multivariable association with echocardiography measures revealed a positive correlation of MR severity with both cellular and geometric changes (e.g., aVICs, EndMT, leaflet thickness, leaflet tenting). Finally, proteomic changes associated with EndMT showed gene-ontology enrichment in vesicle-, inflammatory- and oxidative stress-related processes. This discovery approach indicated new candidate proteins associated with EndMT regulation in IMR. Conclusion: We describe an atypical cellular composition and distinctive proteome of human MVs from patients with IMR, which highlighted new candidate proteins implicated in EndMT-related processes, associated with maladaptive MV fibrotic remodeling.
2021-08-13 | PXD025096 | Pride
Project description:In atrial fibrillation, disturbed electrical conduction disrupts the coordinated contraction of the heart’s antechambers, increasing the risk of stroke and heart failure. The rising prevalence of this disease approaches 9% in patients >65 years. Studying freshly isolated human atrial tissue and a new mouse model, we here decipher how immune and stromal cells contribute to the structural tissue remodeling that underlies atrial fibrillation. Single-cell transcriptomes from control and diseased human atria documented macrophage doubling at the expense of endothelial and mural cells. An inflammatory monocyte and a pro-fibrotic SPP1+ macrophage cluster expanded in patients with atrial fibrillation. To experimentally perturb pathways observed in patients, we matched their risk factors Hypertension, Obesity and Mitral valvE Regurgitation (HOMER) in mice. Atrial single-cell transcriptomes obtained in HOMER mice, which developed enlarged, fibrillation-prone atria, recapitulated human cell composition and transcriptome variations. Recruitment drove the expansion of atrial macrophages; accordingly, inhibition of monocyte migration reduced arrhythmia in Ccr2-/- HOMER mice. Deleting Spp1 established macrophage-derived osteopontin as a pleiotropic signal that promotes atrial fibrillation through pro-fibrotic, inflammatory crosstalk with an arsenal of local immune and stromal cells. Taken together, we identify SPP1+ macrophages as targets for immunomodulatory therapy in atrial fibrillation.
2023-07-13 | GSE225671 | GEO
Project description:In atrial fibrillation, disturbed electrical conduction disrupts the coordinated contraction of the heart’s antechambers, increasing the risk of stroke and heart failure. The rising prevalence of this disease approaches 9% in patients >65 years. Studying freshly isolated human atrial tissue and a new mouse model, we here decipher how immune and stromal cells contribute to the structural tissue remodeling that underlies atrial fibrillation. Single-cell transcriptomes from control and diseased human atria documented macrophage doubling at the expense of endothelial and mural cells. An inflammatory monocyte and a pro-fibrotic SPP1+ macrophage cluster expanded in patients with atrial fibrillation. To experimentally perturb pathways observed in patients, we matched their risk factors Hypertension, Obesity and Mitral valvE Regurgitation (HOMER) in mice. Atrial single-cell transcriptomes obtained in HOMER mice, which developed enlarged, fibrillation-prone atria, recapitulated human cell composition and transcriptome variations. Recruitment drove the expansion of atrial macrophages; accordingly, inhibition of monocyte migration reduced arrhythmia in Ccr2-/- HOMER mice. Deleting Spp1 established macrophage-derived osteopontin as a pleiotropic signal that promotes atrial fibrillation through pro-fibrotic, inflammatory crosstalk with an arsenal of local immune and stromal cells. Taken together, we identify SPP1+ macrophages as targets for immunomodulatory therapy in atrial fibrillation.
2023-07-13 | GSE224947 | GEO