Failing heart-specific cardiac fibroblasts induce heart failure via c-Myc
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ABSTRACT:
PROVIDER: PRJNA1068679 | ENA |
REPOSITORIES: ENA
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Project description:Failing heart-specific cardiac fibroblasts induce heart failure via c-Myc Expansion [snRNA-seq]
| PRJNA1290106 | ENA
Project description:Heart failure (HF) is a global concern, marked by limited therapeutic options. While existing studies primarily focus on cardiomyocytes, there is a notable absence of drugs targeting noncardiomyocytes for HF. We focused on cardiac fibroblasts (CFs), utilising single-cell RNA-sequencing analysis. The analysis of murine hearts revealed one subcluster exclusive to the HF stage. The transcription factor c-Myc is specifically expressed in heart failure-specific fibroblasts (HF-Fibro). Cardiac fibroblast-specific deletion of c-Myc ameliorates pressure overload-induced cardiac dysfunction without affecting fibrosis. To elucidate the molecular function of c-Myc in HF-Fibro, transcriptome analysis by RNA-seq was conducted, in vivo.
2025-07-17 | GSE254172 | GEO
Project description:Heart failure (HF) is a major global problem with increasing numbers of patients and deaths in many countries. Existing studies on HF have focused primarily on cardiomyocytes, with few studies targeting non-cardiomyocytes. This study focused on cardiac fibroblasts (CFs) as a cause of HF. Single-cell RNA sequencing of mouse hearts revealed six distinct subclusters of CFs at various stages after pressure overload, with one subcluster being specific to the HF stage. The transcription factor c-Myc is specifically expressed in HF-specific CFs. CFs-specific deletion of c-Myc ameliorates pressure overload-induced cardiac dysfunction without affecting fibrosis. The chemokine Cxcl1 is highly expressed in HF-specific CFs and downregulated in CFs-specific c-Myc knockout mice. Chromatin immunoprecipitation analysis revealed that c-Myc binds to the promoter region of Cxcl1 in CFs. Cxcr2, the receptor for Cxcl1, is expressed in cardiomyocytes, and blockade of the Cxcl1-Cxcr2 signalling pathway prevents pressure overload-induced cardiac dysfunction. The addition of CXCL1 reduces the contractility of cardiomyocytes of neonatal rats and human iPS-derived cardiomyocyte organoids. Human CFs from failing hearts expressed c-MYC and CXCL1, while CFs from control hearts did not. These findings suggest that HF-specific CFs play an important role in inducing HF by upregulating c-Myc and Cxcl1 and that CFs could be a novel therapeutic target for HF.
2025-07-18 | GSE302337 | GEO
Project description:LCMS files from tryptic digests of ~1-4 mg piece of heart ventricular tissue from human with ischemic heart failure and non-failing controls.
Specimen number correspond to .raw files as follows:
Ischemic Heart failure -
54687.1; HF_1_phos.raw
53148.1; HF_2_phos.raw
53589.2; HF_3_phos.raw
54146.1; HF_4_phos.raw
52935.1; HF_5_phos.raw
Non-failing -
52941.1; NHF_1_phos.raw
52777.1; NHF_2_phos.raw
53019.2; NHF_3_phos.raw
53058.1; NHF_4_phos.raw
52621.1; NHF_5_phos.raw
2022-12-07 | MSV000090858 | MassIVE
Project description:Aim - Pathological cardiac remodeling is characterized by cardiomyocyte hypertrophy and fibroblast activation, which can ultimately lead to heart failure (HF). Genome-wide expression analysis on heart tissue has been instrumental for the identification of molecular mechanisms at play. However, these data were based on signals derived from all cardiac cell types. Here we aimed for a more detailed view on molecular changes driving cardiomyocyte hypertrophy and failure to aid in the development of therapies to reverse maladaptive remodeling. Methods and results - Utilizing cardiomyocyte-specific reporter mice exposed to pressure overload by transverse aortic banding (TAB), we obtained gene expression profiles of hypertrophic (one-week TAB) and failing (eight-weeks TAB) cardiomyocytes. We identified subsets of genes differentially regulated and specific for either stage. Among these, we found upregulation of known marker genes for HF, such as Nppb and Myh7. Additionally, we identified a set of genes specifically upregulated in failing cardiomyocytes and that so far have not been studied in HF, including the platelet isoform of phosphofructokinase (PFKP). Human cardiomyocytes subjected to 7-day NE/AngII treatment recapitulated the upregulation of the failure-induced genes indicating conservation. RNA-seq on failing and healthy human hearts confirmed increased expression for several failure-induced genes and allowed for expressional correlation to NPPB/MYH7. Finally, suppression of Pfkp in PE-treated primary cardiomyocytes reduced stress-induced gene expression and hypertrophy, suggesting a role in cardiomyocyte failure. Conclusion - Using cardiomyocyte-specific transcriptomic analysis we identified novel failure-induced genes relevant for human HF, and show that PFKP is a conserved failure-induced gene that can modulate cardiomyocyte stress response.
2020-09-15 | GSE138299 | GEO
Project description:We aim to study the gene alteration in diabetic failing heart and decipher the molecular mechanisms underlying diabetes-associated heart failure. Diabetic patients are more vulnerable to cardiac dysfunction. The pathogenesis of diabetes-associated heart failure is multiple, including cardiac pathological remodeling, intracellular metabolic disorders, cardiac inflammation, etc. To determine which signaling pathways causes the myocardial alterations, we plan to identify the individual gene function during the pathogenesis using an unbiased large-scale screening. Firstly, gene expression should be assessed. RNA-seq is used to detect gene changes, afterwards, the potential candidates involved in the molecular basis induing diabetic heart failure will be validated by other assessment and function study will be performed to explore their role in the onset and progression of heart failure in diabetes. Samples are healthy subject versus those with diabetes with cardiovascular disease (CVD) and heart failure (HF)
2026-08-14 | E-MTAB-16712 | biostudies-arrayexpress
Project description:The microtubule (MT) cytoskeleton can provide a mechanical resistance that can impede the motion of contracting cardiomyocytes. Yet a role of the MT network in human heart failure is unexplored. Here we utilize mass spectrometry to characterize changes to the cytoskeleton in human heart failure. Proteomic analysis of left ventricle tissue reveals a consistent upregulation and stabilization of intermediate filaments and MTs in human heart failure. This dataset includes left ventricular (LV) myocardium from 34 human hearts – either non-failing (NF) or failing hearts. NF hearts are subdivided into normal or compensated hypertrophy (cHyp), while failing hearts are subdivided into ischemic cardiomyopathy (ICM), dilated cardiomyopathy (DCM), and hypertrophic cardiomyopathy with preserved or reduced ejection fraction (HCMpEF and HCMrEF, respectively). Further details on patient classification and in vivo parameters on each heart are listed in sample details.txt.
2018-06-06 | PXD008934 | Pride
Project description:Mitochondrial proteomics was used to identify energy metabolic derangements that occur during the early stages of heart failure in well-defined mouse models. Levels of β-hydroxybutyrate dehydrogenase 1 (BDH1), a key enzyme in ketone oxidation, was upregulated. 13C-substrate flux studies and metabolomic profiling confirmed that the hypertrophied and early stage failing heart shifts to ketone bodies as a fuel source in the context of reduced oxidation of fatty acids, the chief substrate for the normal heart. This fuel shift is associated with an expansion of the acetyl pool and reduced levels of NAD+ levels resulting in increased mitochondrial protein acetylation. Myocardium of humans with heart failure also exhibited mitochondrial protein hyperacetylation. We propose that a shift to ketones as a fuel source leads to maladaptive bioenergetic consequences during the development of heart failure.
2016-02-26 | PXD001652 | Pride
Project description:To provide comprehensive characterization of the cardiac proteome of advanced human heart failure, we performed mass spectrometry-based label free proteomic analysis of left ventricular samples obtained from 149 human heart failure patients and 9 non-failing controls. All heart failure biopsy samples were collected at the time of heart transplantation or assist device implantation. To characterize signaling perturbations, we performed phosphoproteomic analysis for 32 representative heart failure samples and 8 non-failing controls.
2026-08-21 | PXD068439 | Pride
Project description:Epigenetic status has been linked to cardiac hypertrophy and heart failure. Histone deacetylase inhibitors are promising drugs for preventing cardiac remodeling. We previously demonstrated very different patterns of histone H3 lysine 9 trimethylation (H3K9me3) and histone H3 lysine 4 trimethylation (H3K4me3) in failing hearts compared to control hearts in both animal models and clinical heart specimens. Here, we focused on a heart failure-specific histone modification, H3K9me3, and investigated the prognostic efficacy of administering a histone H3K9 methyltransferase inhibitor, chaetocin, to Dahl salt-sensitive rats, an animal model of heart failure. Chaetocin delayed the timing of transition from cardiac hypertrophy to heart failure, and prolonged survival in this animal model. Mitochondrial dysfunction was improved with inhibitor use in the failing heart. ChIP-seq analysis demonstrated that heart failure caused an increase in H3K9me3 alignments in thousands of repetitive elements, including regions neighboring mitochondrial genes, and a corresponding reduction of this effect with inhibitor use. However, at 35 loci, heart failure was conversely associated with a reduction in H3K9me3 alignments, and inhibitor use reversed this effect. These data suggest that excessive heterochromatinization of repetitive elements in the failing heart might impair pumping function with mitochondrial gene silencing. H3K9 methyltransferase inhibitors may be a promising novel therapy for chronic heart failure.
2015-05-31 | GSE69194 | GEO