Alterations in cardiac DNA methylation in human dilated cardiomyopathy
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE42510 | GEO | 2012/12/18
SECONDARY ACCESSION(S): PRJNA182172
REPOSITORIES: GEO
Similar Datasets
Project description:This project analyzes genome-wide cardiac DNA methylation in patients with idopathic DCM and control individuals Given are datafiles from n = 8 controls (patients after Htx) and n = 9 patients with idopathic DCM. The datasets have been normalized together with other beadchip files not subject to this study. Methylation profiles were generated from human left ventricular myocardium DNA.
2012-12-18 | E-GEOD-42510 | biostudies-arrayexpress
Project description:Background - Cardiac microRNAs (miRNAs) could be released into circulation thus becoming circulating cardiac miRNAs, which are increasingly recognized as noninvasive and readily accessible biomarker for multiple heart diseases. A global loss of cardiac miRNAs due to dicer or dgcr8 depletion has been reported to lead to dilated cardiomyopathy (DCM). However, DCM-associated circulating miRNAs (DACMs) and their roles in regulating DCM progression remain largely unexplored. Methods and Results - Through miRNA sequencing of human plasma procured from DCM patients and healthy control people, DCM was characterized with a unique expression pattern for circulating miRNAs. Among them, miR-26a-5p, miR-30c-5p, miR-126-5p, and miR-126-3p were all identified with dramatic reductions in DCM mouse myocardium as in the plasma of DCM patients. FOXO3, highlighted as a predicted common target gene, was experimentally demonstrated to be repressed within cardiomyocytes by these miRNAs except miR-26a-5p. Mechanistically, miRNA combination (miR-30c-5p, miR-126-5p, and miR-126-3p) significantly attenuated FOXO3-induced apoptosis and autophagy observed in cardiomyocytes as well as in DCM murine heart. Cardiac-specific knockout of FOXO3 conspicuously mitigated myocardial apoptosis and autophagy in DCM development. Moreover, stymieing the interaction between these miRNAs and FOXO3 mRNA extremely crippled the cardioprotection of these miRNAs against DCM progression. Cardiac miRNA-FOXO3 axis plays a pivotal role in safeguarding against myocardial apoptosis and autophagy, thereby maintaining cardiac homeostasis and potently preventing DCM development. These findings may provide serological clues for the noninvasive diagnosis of DCM in the future, and unambiguously shed new light on DCM pathogenesis and associated therapeutic targets
2022-07-31 | GSE209991 | GEO
Project description:To investigate the physiological characteristics of cardiac fibroblasts (CF) from pediatric dilated cardiomyopathy (DCM) patients, CFs were harvested from left ventricular free wall at the heart transplantation. We then performed RNA-seq for 7 different lines of CFs.
2023-09-12 | GSE223517 | GEO
Project description:This study attempts at investigating the changes in cardiac gene expression that occur in Dilated Cardiomyopathy (DCM). DCM in Dobermans and Boxers are the focus of this study. Control heart tissue as well as Pacing tissue used is from mongrel dogs. Keywords: control vs pacing vs disease; strain specific disease 3 Dobermans-DCM, 4 Boxers-DCM, 3 mongrels-control and 3 mongrels-pacing
2008-05-08 | E-GEOD-11015 | biostudies-arrayexpress
Project description:Dilated cardiomyopathy (DCM), defined by left ventricular (LV) enlargement associated with impaired cardiac performance, is a major cause of heart failure (HF). This results in a dilated, thin-walled left ventricle that fails to supply sufficient blood to the body. Truncating variants in TTN (TTNtv), coding for the largest structural protein in the sarcomere, contribute to the largest portion of familial and ambulatory DCM. The mechanisms for how TTNtv lead to cardiac dilation are unclear. Here, we show that reduction of Ttn expression by shRNA (Ttn shRNA) generated DCM in both mouse and rat. Ttn shRNA transduced mice developed typical DCM manifestations including impaired cardiac performance, enlarged LV and reduced LV wall thickness. Gene profiling indicates cardiac metabolism, cell proliferation and survival related genes are significantly dysregulated in Ttn shRNA-induced DCM. TUNEL assay showed Ttn shRNA induced a significant increase of cardiac cell apoptosis. A screen of 15 dysregulated downstream genes identified candidates, including Esrra, Esrrb and Yy1 significantly suppressed Ttn shRNA-induced cardiac dilation and/or DCM. Ttn shRNA induced cardiac cell apoptosis was ameliorated by Yy1. Importantly, by inducing D-type cyclin, Yy1 initiated cardiomyocyte cell cycle reentry facilitating the restoration of cardiac performance. Our findings demonstrate that DCM caused by Ttn insufficiency can be treated by therapeutically enhancing cardiac cell proliferation and survival.
2020-03-26 | GSE112319 | GEO
Project description:Lipid (Plasmalogen) levels can be modulated via a dietary supplement called alkylglycerols (AG) which has demonstrated benefits in some disease settings. However, its therapeutic potential in cardiomyopathy remains unknown. This study explored an optimized AG supplement in restoring plasmalogen levels and attenuate cardiac dysfunction/pathology. Here, we placed a cardiac-specific transgenic cardiomyopathy mouse model, with cardiac function and molecular landscape assessed. AG supplementation increased total plasmalogens in DCM hearts and attenuated lung congestion of both sexes, but only prevented cardiac dysfunction in males. This was associated with cardiac and renal enlargement, a more favorable pro-cardiac gene expression profile, and a trend for lower cardiac fibrosis. By lipidomics, specific d18:1 ceramide species associated with cardiac pathology were lower in the DCM hearts from mice on the AG diet, and tetra-linoleoyl cardiolipin, a lipid crucial for mitochondria function was restored with AG supplementation. Proteomic analysis of hearts from male DCM mice receiving AG supplementation revealed enrichment in mitochondrial protein network, as well as upregulation of extracellular matrix binding proteins associated with cardiac regeneration. Here we highlight that AG supplementation restored plasmalogens in DCM hearts, but showed greater therapeutic potential in males than females
2024-08-08 | MSV000095560 | MassIVE
Project description:Dilated cardiomyopathy (DCM) and heart failure are associated with mitochondrial dysfunction and dysregulated lipid metabolism. Recent studies have implicated a pivotal role of Hippo pathway activation in the development of DCM with profound metabolic remodelling. However, alterations in the cardiac lipid profile and responsible molecular mechanisms, including upregulated galectin-3, remain unclear in the setting of DCM. Mice with DCM induced by Hippo pathway activation (Mst1 gene overexpression alone or with galectin-3 gene deletion) were studied by lipidomic profiling, transcriptomic profiling and immunoblotting for mRNA and protein expression. Profound alterations in cardiac lipid classes were observed, notably elevated sphingolipids, reduced triacylglycerol (TG) and ether lipids, alterations in phospholipid species, elevated lysophosphatidylcholine, and a profound reduction in mitochondria-specific cardiolipin and coenzyme Q10. Relative to adult mice with advanced DCM, reduced TG content was evident but sphingolipid accumulation was absent in young mice at early phase of DCM. Mechanistically, the lipidomic profile in DCM heart was in consistent with dysregulated expression of specific gene sets for biosynthesis of ceramides or TG, TG storage/hydrolysis, mitochondrial lipid metabolism, peroxisome biogenesis, and suppressed PPAR-alpha signaling. Furthermore, galectin-3 gene deletion resulted in changes in some lipid classes and numerous lipid species in settings of healthy and DCM. Multiple alterations in cardiac lipids were identified by lipidomics in a mouse model of DCM due to activation of the Hippo pathway. By employing transcriptome and galectin-3 gene deletion, we revealed underlying mechanisms for lipid abnormalities involving upregulated galectin-3, downregulated expression of specific gene sets of lipid metabolism, and attenuated PPAR-alpha signaling.
2022-09-22 | GSE213707 | GEO
Project description:Dilated cardiomyopathies (DCM) show remarkable variability in their age of onset, phenotypic presentation, and clinical course. Hence, disease mechanisms must exist that modify the occurrence and progression of DCM, either by genetic or epigenetic factors that may interact with environmental stimuli. In the present study, we examined genome-wide cardiac DNA methylation in patients with idiopathic DCM and controls. We detected methylation differences in pathways related to heart disease, but also in genes with yet unknown function in DCM or heart failure, namely Lymphocyte antigen 75 (LY75), Tyrosine kinase-type cell surface receptor HER3 (ERBB3), Homeobox B13 (HOXB13) and Adenosine receptor A2A (ADORA2A). Mass-spectrometric analysis and bisulphite-sequencing enabled confirmation of the observed DNA methylation changes in independent cohorts. Aberrant DNA methylation in DCM patients was associated with significant changes in LY75 and ADORA2A mRNA expression, but not in ERBB3 and HOXB13. In vivo studies of orthologous ly75 and adora2a in zebrafish demonstrate a functional role of these genes in adaptive or maladaptive pathways in heart failure.
| S-EPMC3598081 | biostudies-literature
Project description:This study attempts at investigating the changes in cardiac gene expression that occur in Dilated Cardiomyopathy (DCM). DCM in Dobermans and Boxers are the focus of this study. Control heart tissue as well as Pacing tissue used is from mongrel dogs. Keywords: control vs pacing vs disease; strain specific disease
2008-05-08 | GSE11015 | GEO
Project description:Loss of Bcl2-associated anthanogene 3 (BAG3) is associated with dilated cardiomyopathy (DCM). Recent studies show that BAG3 regulates sarcomere protein turnover in cardiomyocytes (CMs). However, the function of BAG3 in other cell types of the heart is unknown. In this study, we used an isogenic pair of BAG3 knockout and wild-type human induced pluripotent stem cells (hiPSC) to interrogate the function of BAG3 in hiPSC-derived cardiac fibroblasts (CFs). Generating a series of conditional knockout (cKO) engineered heart tissues, we determined the contribution of CF BAG3 to engineered heart tissue function. Despite normal CM genotype, the loss of fibroblast-specific BAG3 (FBKO) caused a reduction in contractile force and an increase in cardiac fibrosis in the engineered heart tissues, recapitulating the phenotype of DCM. Using culture substrates with defined stiffness, we decoupled the mechanical activation of fibroblasts from their ligand response. In BAG3-/- CFs, we observed an increased sensitivity to transforming growth factor β (TGFβ) signaling and activation of a fibrogenic response when cultured at physiological stiffness (8kPa). Mechanistically, loss of BAG3 increased transforming growth factor receptor 2 (TGFBR2) levels. BAG3 binds TGFBR2 and mediates its ubiquitination and proteasomal degradation. To further validate these results, we performed single-nuclei sequencing of cardiac tissue from DCM patients carrying pathogenic BAG3 mutations. Mutations in BAG3 increased fibrotic gene expression in cardiac fibroblasts. Together, these results extend our understanding of the roles of BAG3 in heart disease beyond the cardiomyocyte-centric view. This study also highlights the ability of hiPSC-based models and tissue engineering to answer questions about the cell-type specific aspects of cardiac disease.
2024-09-16 | GSE261750 | GEO