Chromatin Remodelers in Cardiometabolic Heart Failure with Preserved Ejection Fraction
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE289265 | GEO | 2025/06/05
REPOSITORIES: GEO
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Project description:Recent studies have suggested that epicardial adipose tissue (EAT) play an important role in the pathogenesis of heart failure with preserved ejection fraction (HFpEF), but few have characterized the underlying mechanism between their interactions. Recent evidence suggested that molecules secreted from EAT, including exosomes carrying non-coding RNAs (ncRNAs), may participate in the development of HFpEF. The aim of the present study was to investigate the expression profile of mRNAs and ncRNAs in EAT with HFpEF.
2022-01-05 | GSE192886 | GEO
Project description:BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) accounts for 50% of heart failure patients. Clinically, HFpEF prevalence show age and gender biases. Although the majority of HFpEF patients are elderly, there is an emergence of young HFpEF patients. A better understanding of the underlying pathogenic mechanism is urgently needed. Here, we aimed to determine the role of aging in the pathogenesis of HFpEF. METHODS AND RESULTS: HFpEF dietary regimen (HFD + L-NAME) was used to induce HFpEF in wildtype and telomerase RNA knockout mice (mTRG2 and mTRG3), an aging murine model. First, both male and female animals develop HFpEF equally. Second, cardiac wall thickening preceded diastolic dysfunction in all HFpEF animals. Third, accelerated HFpEF onset was observed in mTRG2 (at 6-weeks) and mTRG3 (at 4-weeks) compared to wildtype (8-weeks). Fourth, we demonstrate that mitochondrial respiration transitioned from compensatory state (normal basal yet loss of maximal respiratory capacity) to dysfunction (loss of both basal and maximal respiratory capacity) in a p53 dosage dependent manner. Last, using myocardial-specific p53 knockout animals, we demonstrate that p53 is necessary for the development of HFpEF. CONCLUSIONS: Here we demonstrate that p53 activation is critical for the pathogenesis of HFpEF. We show that short telomere animals exhibit a basal level of p53 activation, mitochondria upregulate mtDNA encoded genes as a mean to compensate for blocked mitochondrial biogenesis, and loss of myocardial p53 prevents HFpEF upon HFD + L-NAME challenge.
2022-07-06 | GSE195482 | GEO
Project description:Background: Heart failure with preserved ejection fraction (HFpEF) constitutes more than half of all heart failure but has few effective therapies. Recent human myocardial transcriptomics and metabolomics have revealed major differences between HFpEF, HF with reduced EF (HFrEF), and controls. How this translates at the protein level is currently unknown. Methods: Myocardial tissue from patients with HFpEF and non-failing donor controls was analyzed by data-dependent (DDA, n=10 HFpEF, n=9 controls) and data-independent (DIA, n=44 HFpEF, n=5 controls) mass spectrometry-based proteomics. Previously reported myocardial proteomic data from end-stage HFrEF and controls were also used. Differential protein expression analysis, machine learning and pathway enrichment were integrated with clinical characteristics and myocardial transcriptomics. Results: DDA-MS proteomics identified 88 significantly upregulated and 248 down-regulated proteins in HFpEF vs controls, out of 1996 identified proteins. Principal component analysis of DDA-MS proteomics found HFpEF was separated into 2 sub-groups: one being similar to controls the other quite disparate. Top proteins contributing to the separation of HFpEF subgroups were enriched in actin/myosin binding, regulation of DNA replication/repair, transcription, and translation. Downregulated proteins in HFpEF vs controls were enriched in pathways related to ribosome structure, transmembrane transporters, metabolic enzymes, and oxidative phosphorylation (OxPhos) proteins. Enriched pathways for proteins upregulated in HFpEF related to actin and phospholipid binding, growth factor signaling, kinase regulation, and glycolysis. Ingenuity pathway analysis predicted downregulation of protein translation, mitochondrial function, and glucose and fat metabolism in HFpEF. OxPhos gene (increased) versus protein (decreased) expression was discordant in HFpEF. The second DIA proteomic analysis also yielded two HFpEF sub-groups; the one most different from controls also having reduced OxPhos and protein translation pathways. A higher proportion of these patients also had severe obesity. Conclusions: Integrative proteomics, transcriptomics, and pathway analysis supports a translational defect particularly involving mitochondrial, ribosomal and protein translation proteins in HFpEF. Patients with more distinct proteomic signatures from control were more often very obese. The results support therapeutic efforts targeting metabolism, mitochondrial function, and protein translation in this subgroup.
2025-04-11 | PXD060431 | Pride
Project description:Heart failure affects 2–3% of adult Western population. Prevalence of heart failure with preserved left ventricular (LV) ejection fraction (HFpEF) increases. Studies suggest HFpEF patients to have altered myocardial structure and functional changes such as incomplete relaxation and increased cardiac stiffness. We hypothesised that patients undergoing elective coronary bypass surgery (CABG) with HFpEF characteristics will show distinctive gene expression compared to patients with normal LV physiology. Myocardial biopsies for mRNA expression analysis were obtained from sixteen patients with LV ejection fraction ≥ 45%. Five out of 16 patients (31%) had echocardiographic characteristics and increased NTproBNP levels indicative of HFpEF and this group was used as HFpEF proxy, while 11 patients had Normal LV physiology. Utilising principal component analysis, the gene expression data clustered into two groups, corresponding to HFpEF proxy and Normal physiology, and 743 differentially expressed genes were identified. The associated top biological functions were cardiac muscle contraction, oxidative phosphorylation, cellular remodelling and matrix organisation. Our results also indicate that upstream regulatory events, including inhibition of transcription factors STAT4, SRF and TP53, and activation of transcription repressors HEY2 and KDM5A, could provide explanatory mechanisms to observed gene expression differences and ultimately cardiac dysfunction in the HFpEF proxy group. <br> Sequencing data from clinical patients fall under GDPR regulations of sharing of personal data and will be made available through EGA-SE.
2019-03-02 | E-MTAB-7454 | biostudies-arrayexpress
Project description:Cardiometabolic heart failure with preserved ejection fraction (cHFpEF) is highly prevalent and associated with a poor outcome. Pathological gene expressions in heart failure are accompanied by changes in active histone marks without major alterations in DNA methylation. Histone 3 trimethylation at lysine 36 (H3k36me3) - a chromatin signature induced by the histone methyltransferase SETD2 – has shown a strong correlation with changes in gene expression in the human failing heart; yet its role in cardiac disease is poorly understood. The present study investigates the role of SETD2/ H3k36me3 in cHFpEF.
2025-02-12 | GSE289331 | GEO
Project description:As patients with heart failure with preserved ejection fraction (HFpEF) present with multiple comorbidities, we hypothesized, that metabolic syndrome in aging animals could lead to the development of diastolic dysfunction and HFpEF. HFpEF is a common complex morbid syndrome for which there are currently little evidence-based therapies. Obesity-prone rats were exposed to high-fat diet and compared to obesity-resistant rats fed with standard chow. Phenotyping of metabolic syndrome, associated with echocardiographic and cardiac hemodynamic measurements, was performed after 4 and 12 months. Blood and myocardial tissue sampling were performed for pathobiological evaluation. High-fat diet in obesity-prone rats elicited metabolic syndrome, characterized by increased body and abdominal fat weights, glucose intolerance and hyperlipidemia, as well as increased left ventricular (LV) systolic pressure (after 12 months). This was associated with LV diastolic dysfunction (assessed by increased LV end-diastolic pressure) and pulmonary hypertension (assessed by increased right ventricular systolic pressure). Echocardiography revealed significant concentric LV hypertrophy, while LV ejection fraction was preserved. LV remodeling was associated with cardiomyocyte hypertrophy, as well as myocardial and perivascular fibrosis. Circulating levels of soluble ST2 markedly increased in rats with HFpEF, while plasma NT-proBNP levels decreased. RNA-sequencing analysis identified clusters of genes implicated in fatty acid metabolism and calcium-dependent contraction as upregulated pathways in the myocardium of rats with HFpEF. High-fat diet during 12 months in obesity-prone rats led to the development of a relevant preclinical model of HFpEF with multiple comorbidities, suitable for investigating novel therapeutic interventions.
2022-02-02 | GSE189190 | GEO
Project description:To understand the cellular mechanisms of heart failure with preserved ejection fraction (HFpEF), We investigated the functional outcome and the underlying mechanisms from concurrent mechanic and metabolic stresses in the heart by applying transverse aortic constriction (TAC) in lean C57Bl/6J (HFrEF phenotype) or obese/diabetic B6.Cg-Lepob/J (ob/ob) mice (HFpEF phenotype) followed by single-nuclei RNA-seq (snRNA-seq) and targeted manipulation of a top ranked signaling pathway (glucagon receptor signaling) differentially affected in the two experimental cohorts.
2024-07-12 | GSE270896 | GEO
Project description:Heart failure with preserved ejection fraction (HFpEF) accounts for ~50% of all heart failure cases. HFpEF is a heterogeneous condition with poorly understood molecular mechanisms related to different forms including acute and chronic HFpEF. Here, we utilised plasma samples collected from patients with different forms of HFpEF to identify unique molecular mechanisms and pathways. We performed unbiased, comprehensive proteomic analyses of 31 gender- and BMI-matched plasma samples from patients with acute HFpEF (n=8), chronic HFpEF (n=9) and hypertrophic cardiomyopathy (HCM; n=14). We identified leucine-rich alpha-2-glycoprotein 1 (LRG1) as an aberrant protein across all three forms of HFpEF. We reported perturbations in signalling pathways in HFpEF mainly driven by complement/coagulation/protease and extracellular matrix (ECM) proteins, highlighting the haemostatic disturbances, notably platelet degranulation caused by systematically elevated platelet cytosolic Ca2+. We provided a publicly available online application (https://hao-chen-uts-99171821.shinyapps.io/HFpEF-Proteomics/) of our findings.
2023-03-11 | PXD024012 | Pride
Project description:In this study, we compared the expression profiles of circulating miRNAs in blood samples from controls and patients with heart ailment. Subject with no past history of heart failure/disease are considered as controls. The patients were classified according to the percentage of left ventricular ejection fraction. Patients were grouped as heart failure with reduced (hfREF) and preserved (hfPEF) left ventricular ejection fraction. Employing miRNA microarray, we identified 'signature miRNAs' in peripheral blood samples that distinguished Heart failure from the non-heart failure controls, as well as those of hfREF and hfPEF groups.
2015-02-12 | GSE53437 | GEO
Project description:Heart failure with preserved ejection fraction (HFpEF) is increasingly common but its pathogenesis is poorly understood. The ability to assess genetic and pharmacologic interventions is hampered by the lack of robust pre-clinical mouse models of human HFpEF. We have developed a novel “2-hit” mouse model, which combines obesity and insulin resistance with chronic pressure overload to recapitulate clinical features of HFpEF. C57Bl6/NJ mice fed a high fat diet for at least 10 weeks were administered an AAV8-driven vector resulting in constitutive overexpression of mouse Renin1d. Control mice, HFD only, Renin only and HFD-Renin (aka “HFpEF”) littermates underwent a battery of cardiac and extracardiac phenotyping. HFD-Renin mice demonstrated obesity and insulin resistance, a 2-3-fold increase in circulating renin levels and resulted in 30-40% increase in LVH hypertrophy, preserved systolic function, and diastolic dysfunction indicated by altered E/e’, IVRT, and strain measurements; increased left atrial mass; elevated natriuretic peptides; and exercise intolerance. The transcriptomic and metabolomic signature of HFpEF indicates upregulation of fibrotic pathways and downregulation of metabolic pathways, in particular branched chain amino acid catabolism, similar to human HFpEF data. Treatment of these mice with the sodium-glucose cotransporter 2 inhibitor empagliflozin, a powerful but incompletely understood HFpEF therapy, showed improvement in exercise tolerance, left heart enlargement, and insulin homeostasis. The HFD-Renin mouse model recapitulates many critical features of human HFpEF and allows for dissection of how individual pathogenic drivers contribute to cardiac and peripheral metabolic changes. Multiple HFpEF models will also allow for orthogonal studies and increase validity in pre-clinical research efforts.
2025-01-01 | GSE269053 | GEO