Failing heart-specific cardiac fibroblasts induce heart failure via c-Myc
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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:To identify a novel target for the treatment of heart failure, we examined gene expression in the failing heart. Among the genes analyzed, 12/15 lipoxygenase (12/15-LOX) was markedly up-regulated in heart failure. To determine whether increased expression of 12/15-LOX causes heart failure, we established transgenic mice that overexpressed 12/15-LOX in cardiomyocytes. Echocardiography showed that 12/15-LOX transgenic mice developed systolic dysfunction. Cardiac fibrosis increased in 12/15-LOX transgenic mice with advancing age, and was associated with the infiltration of macrophages. Consistent with these observations, cardiac expression of monocyte chemoattractant protein-1 (Mcp-1) was up-regulated in 12/15-LOX transgenic mice compared with wild-type mice. Treatment with 12-hydroxy-eicosatetraenotic acid, a major metabolite of 12/15-LOX, increased MCP-1 expression in cardiac fibroblasts and endothelial cells, but not in cardiomyocytes. Inhibition of Mcp-1 reduced the infiltration of macrophages into the myocardium and prevented both systolic dysfunction and cardiac fibrosis in 12/15-LOX transgenic mice. Likewise, disruption of 12/15-LOX significantly reduced cardiac Mcp-1 expression and macrophage infiltration, thereby improving systolic dysfunction induced by chronic pressure overload. Our results suggest that cardiac 12/15-LOX is involved in the development of heart failure and that inhibition of 12/15-LOX could be a novel treatment for this condition. Heart failure is still one of the leading causes of death worldwide. Therefore, it is important to elucidate the underlying mechanisms of heart failure and develop more effective treatments for this condition. To clarify the molecular mechanisms of heart failure, we performed microarray analysis using cardiac tissue samples obtained from a hypertensive heart failure model (Dahl salt-sensitive rats). ~300 genes showed significant changes of expression in the failing hearts compared with control hearts. Among the genes analyzed, 12/15-lipoxygenase (12/15-LOX) was most markedly up-regulated in failing hearts compared with control hearts .
2009-06-06 | E-GEOD-16199 | biostudies-arrayexpress
Project description:Tissue fibrosis and organ dysfunction are hallmarks of age-related diseases including heart failure, but it remains elusive whether there is a common pathway to induce both events. Through single-cell RNA-seq, spatial transcriptomics, and genetic perturbation, we elucidate that high-temperature requirement A serine peptidase 3 (Htra3) is a critical regulator of cardiac fibrosis and heart failure by maintaining the identity of quiescent cardiac fibroblasts through degrading transforming growth factor-β (TGF-β). Pressure overload downregulates expression of Htra3 in cardiac fibroblasts and activated TGF-β signaling, which induces not only cardiac fibrosis but also heart failure through DNA damage accumulation and secretory phenotype induction in failing cardiomyocytes. Overexpression of Htra3 in the heart inhibits TGF-β signaling and ameliorates cardiac dysfunction after pressure overload. Htra3-regulated induction of spatio-temporal cardiac fibrosis and cardiomyocyte secretory phenotype are observed specifically in infarct regions after myocardial infarction. Integrative analyses of single-cardiomyocyte transcriptome and plasma proteome in human reveal that IGFBP7, which is a cytokine downstream of TGF-β and secreted from failing cardiomyocytes, is the most predictable marker of advanced heart failure. These findings highlight the roles of cardiac fibroblasts in regulating cardiomyocyte homeostasis and cardiac fibrosis through the Htra3-TGF-β-IGFBP7 pathway, which would be a therapeutic target for heart failure.
2022-03-03 | GSE168742 | GEO
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:Heart failure is a leading cause of cardiovascular mortality with limited options for treatment. We analyzed whether the anti-ischemic drug ranolazine could retard the progression of heart failure in an experimental model of heart failure induced by 6 months of chronic pressure overload. The study showed that 2 months of ranolazine treatment improved cardiac function of aortic constricted C57BL/6J (B6) mice with symptoms of heart failure as assessed by echocardiography. The microarray gene expression study of heart tissue from failing hearts relative to ranolazine-treated and healthy control hearts identified heart failure-specific genes that were normalized during treatment with the anti-ischemic drug ranolazine. Microarray gene expression profiling was performed with heart tissue isolated from three study groups: (i) untreated 10 month-old C57BL/6J (B6) mice with heart failure induced by 6 months of abdominal aortic constriction (AAC), (ii) 10 month-old B6 mice with 6 months of AAC and two months of treatment with the anti-ischemic drug ranolazine (200 mg/kg), and (iii) age-matched, untreated, sham-operated B6 control mice.
2010-12-03 | E-GEOD-25766 | biostudies-arrayexpress
Project description:Heart failure is a leading cause of cardiovascular mortality with limited options for treatment. We analyzed whether the anti-ischemic drug ranolazine could retard the progression of heart failure in an experimental model of heart failure induced by 6 months of chronic pressure overload. The study showed that 2 months of ranolazine treatment improved cardiac function of aortic constricted C57BL/6J (B6) mice with symptoms of heart failure as assessed by echocardiography. The microarray gene expression study of heart tissue from failing hearts relative to ranolazine-treated and healthy control hearts identified heart failure-specific genes that were normalized during treatment with the anti-ischemic drug ranolazine.
2010-12-03 | GSE25766 | GEO
Project description:Atherosclerosis and pressure overload are major risk factors for the development of heart failure in patients. Cardiac hypertrophy often precedes the development of heart failure. However, underlying mechanisms are incompletely understood. To investigate pathomechanisms underlying the transition from cardiac hypertrophy to heart failure we used experimental models of atherosclerosis- and pressure overload-induced cardiac hypertrophy and failure, i.e. apolipoprotein E (apoE)-deficient mice, which develop heart failure at an age of 18 months, and non-transgenic C57BL/6J (B6) mice with heart failure triggered by 6 months of pressure overload induced by abdominal aortic constriction (AAC). The development of heart failure was monitored by echocardiography, invasive hemodynamics and histology. The microarray gene expression study of cardiac genes was performed with heart tissue from failing hearts relative to hypertrophic and healthy heart tissue, respectively. The microarray study revealed that the onset of heart failure was accompanied by a strong up-regulation of cardiac lipid metabolism genes involved in fat synthesis, storage and oxidation. Microarray gene expression profiling was performed with heart tissue isolated from (i) 18 month-old apoE-deficient mice relative to age-matched non-transgenic C57BL/6J (B6) mice, (ii) 6 month-old apoE-deficient mice with 2 months of chronic pressure overload induced by abdominal aortic constriction (AAC) relative to sham-operated apoE-deficient mice and nontransgenic B6 mice, (iii) 10 month-old B6 mice with 6 months of AAC relative to sham-operated B6 mice, and (iv) 5 month-old B6 mice with 1 month of AAC relative to age-matched B6 mice.
2010-12-03 | E-GEOD-25765 | biostudies-arrayexpress