The gene expression profiles associated with worsening left ventricle function after mitral valve repair
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE150661 | GEO | 2020/08/12
REPOSITORIES: GEO
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Project description:Degenerative mitral valve disease (DMVD) is the most common cardiac disease in dogs. Some signaling pathways have been implicated in DMVD, including the serotonin and TGF-beta pathways. We sought to identify additional molecular and metabolic pathways that contribute to DMVD using transcriptomic and metabolomic studies. RNA-seq gene expression evaluated on total RNA isolated from left ventricle (LV) and mitral valve (MV) identified 812 differentially expressed transcripts (DETs) in LV and 263 DETs in MV. Out of 15 transcripts selected for RT-qPCR validation, we confirmed 13. In addition, serum samples were collected for metabolomic evaluation. Endothelial nitric oxide synthase (eNOS) was significantly up-regulated in both LV and MV while the level of circulating asymmetrical dimethyl arginine (ADMA), an endogenous NOS inhibitor, was lower in DMVD. Expressions of matrix metalloproteinases (MMP) and their endogenous inhibitor tissue inhibitor of matrix metallopeptidases (TIMP) were altered. This study demonstrates transcript and metabolite differences consistent with increased nitric oxide (NO) and reactive oxygen species (ROS) production, impaired fatty acid transport and oxidation, and increased glucose uptake and glycolysis in DMVD. Our findings are consistent with metabolic conversion in the DMVD heart from oxidative metabolism to glycolysis along with an increased concentration of NO and ROS activity suggesting an alternative signaling effect. Alterations of redox-sensitive NO signaling may play a role in ECM (ECM) homeostasis via modulating MMP and TIMP expression.
2015-05-29 | GSE64544 | GEO
Project description:The gene expression profiles associated with worsening left ventricle function after mitral valve repair
| PRJNA633114 | ENA
Project description:The mitral valve is a highly complex structure which regulates blood flow from the left atrium to the left ventricle (LV) avoiding a significant forward gradient during diastole or regurgitation during systole. The integrity of the mitral valve is also essential for the maintenance of normal LV size, geometry, and function. Significant advances in the comprehension of the biological, functional, and mechanical behavior of the mitral valve have recently been made. However, current knowledge of protein components in the normal human mitral valve is still limited and complicated by the low cellularity of this tissue and the presence of high abundant proteins from the extracellular matrix. We employed here an integrated proteomic approach to analyse the protein composition of the normal human mitral valve and reported confident identification of 422 proteins, some of which have not been previously described in this tissue. In particular, we described the ability of pre-MS separation technique based on liquid-phase IEF and SDS-PAGE to identify the largest number of proteins. These initial results provide a valuable basis for future studies aimed at analysing in depth the mitral valve protein composition and at investigating potential pathogenetic molecular mechanisms.
2016-08-18 | PXD004397 | Pride
Project description:Rational: We previously reported evidence of endothelial to mesenchymal transition (EndMT) and fibrosis in mitral valve (MV) leaflets at two to six months post-myocardial infarction (MI) in sheep. The onset of these changes and the mechanism of their instigation are not known. Early modulation of EndMT and fibrosis in MV leaflets may limit the development of ischemic mitral regurgitation (IMR) and heart failure. H Objective: To test the hypothesis that circulating molecules present in plasma within days after MI incite EndMT and fibrotic processes in MV leaflets. Method and Results: Ovine MVs harvested 8-10 days after inferior MI (IMI) showed an increase in MV thickness by histology and onset of EndMT, shown by increased CD31/α-smooth muscle actin (α-SMA)+ cells in post-MI MV leaflets (10.5±6.9%) versus sham (2.6±4%). In vitro, post-MI plasma induced EndMT and pro-fibrotic markers and enhanced migration of primary mitral valve endothelial cells (VECs). In contrast, sham plasma did not, despite the presence of TGFβ2 at levels known to induce EndMT in VECs (2 ng/ml). Analysis of sham versus post-MI plasma using a cytokine array revealed a significant drop in the Wnt signaling antagonist secreted frizzled-related protein 3 (sFRP3) in post-MI plasma compared to sham plasma, which was confirmed by ELISA. Addition of recombinant sFRP3 to post-MI plasma reversed its EndMT-inducing effect on mitral VECs, measured by restored VE-cadherin, reduced α-SMA, and reduced TGFβ1-3 expression. Extracellular signal related kinase 1/2 and SMAD2/3 phosphorylation were increased in mitral VEC by post-MI plasma, and both were blocked by supplementing the post-MI plasma with sFRP3. RNA-seq analysis of mitral VECs exposed to post-MI versus sham plasma for 24 hours showed upregulated forkhead box M1 (FOXM1), a transcription factor previously shown to drive fibrosis. FOXM1 was co-localized with CD31 in MV leaflets obtained from sheep at 8-10 days post-MI, which suggests FOXM1 may be linked to EndMT initiation. Blocking FOXM1 with Siomycin A (Sio A) reduced EndMT and pro-fibrotic transcripts in post-MI plasma treated mitral VECs. Finally, post-MI plasma-induced and TGFβ-induced FOXM1 was downregulated by sFRP3. Conclusions: Reduced sFRP3 in post-MI plasma appears to facilitate the onset of TGFβ-driven EndMT and fibrosis in mitral VECs by increasing the transcription factor FOXM1. Restoring sFRP3 levels and/or inhibiting FOXM1 may provide new strategies to minimize maladaptive changes that occur in the MV due to MI.
2022-01-15 | GSE182696 | GEO
Project description:In this study, we carried out a large-scale proteome profiling of human mitral valve tissues resected from patients with mitral valve prolapse.
2015-05-07 | PXD000774 | Pride
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:Evaluation of global expression patterns provides a molecular portrait of mitral valve disease, yields insight into the pathophysiologic aspects of DMVD, and identifies intriguing genes and pathways for further study. (Am J Vet Res 2006;67:1307–1318) Keywords: control vs diseased 4 controls( beagle crosses) and 4 affected (1 Daschund, 1 Lhasa apso, 2 miniature poodles)
2008-05-15 | E-GEOD-11460 | biostudies-arrayexpress
Project description:Evaluation of global expression patterns provides a molecular portrait of mitral valve disease, yields insight into the pathophysiologic aspects of DMVD, and identifies intriguing genes and pathways for further study. (Am J Vet Res 2006;67:1307–1318) Keywords: control vs diseased
2008-05-15 | GSE11460 | GEO
Project description:Mitral valve interstitial Tissue: Myxomatous P2 prolapse of the mitral valve vs. Control
| PRJNA431911 | ENA
Project description:We here report the results of a mitral valve transcriptome study designed to identify genes and molecular pathways involved in development of congestive heart failure (CHF) following myxomatous mitral valve disease (MMVD) in dogs. The study is focused on a cohort of elderly age-matched dogs (n=34, age ~10 years) from a single breed – Cavalier King Charles Spaniels (CKCS) – with a high incidence of MMVD. The cohort comprises 19 dogs (10♀, 9♂) without MMVD-associated CHF, and 15 dogs (6♀, 9♂) with CHF caused by MMVD. I.e. we compare gene expression in breed and age matched groups of dogs, which only differ with respect to CHF status. We identify 56 genes, which are differentially expressed between the two groups. In this list of genes, we confirm an enrichment of genes related to the TNFβ signaling pathway, extracellular matrix organization, vascular development, and endothelium damage, which also have been identified in previous studies. However, the genes with the greatest difference in expression between the two groups are CNTN3 and MYH1. Both genes encode proteins, which are predicted to have an effect on the contractile activity of myocardial cells, which in turn may have an effect on valvular performance and hemodynamics across the mitral valve. This may result in shear forces with impact on MMVD progression.
2023-11-10 | GSE217750 | GEO