Transcriptomic profiling of cardiac tissue in control and HFpEF model mice induced by ISO + L-NAME
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE308625 | GEO | 2026/07/22
REPOSITORIES: GEO
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Project description:HFpEF mouse model was established by a \"double hit\" of L-NAME and high-fat diet (60% fat). 5-week-old C57BL/6N mice were given the above intervention for 5 weeks (Early HFpEF group) or 12 weeks (Advanced HFpEF group). 17-week-old mice fed a normal diet were used as the Control group. After adequate perfusion, the hearts were harvested. Ventricular RNA was extracted for RNA sequencing.
2025-12-31 | E-MTAB-15255 | biostudies-arrayexpress
Project description:Heart failure is a disease with increasing prevalence, while present treatment options, especially for heart failure with preserved ejection fraction (HFpEF), are inadequate. Hypertension and obesity-related metabolic dysfunctions are important risk factors for HFpEF development and progression. Nitro-oleic acid (NO2-OA) impacts metabolic processes by improving glucose tolerance and adipocyte function. We sought to unravel effects of NO2-OA on cardiac function. Mice were fed for 15 weeks with high fat diet combined with endothelial nitric oxide synthase inhibitor (L-NAME). During the last 4 weeks treatment with nitro-oleic acid or vehicle was administered via osmotic pumps. Finally mice were sacrificed, left ventricular tissue harvested, snapfrozen in liquid nitrogen and stored at -80°C until protein isolation.
2025-03-18 | PXD058165 | Pride
Project description:Heart failure (HF) with preserved ejection fraction (HFpEF) comprises heterogenous clinical phenotypes and presence of various co-morbidities. Recent two-hit translational animal models, including the hypertensive, nitrosative-stressed mice fed with high-fat diet and L-NAME (HFD+L-NAME) and the obese-diabetic leptin receptor-deficient db/db mice with excess aldosterone (db/db+Aldo), may phenocopy select subgroups of HFpEF. We systematically compared mechanisms of excitation-contraction coupling (ECC), electrophysiology, and gene transcription in these key preclinical HFpEF models and between sexes to advance translation. We performed morphometry, echocardiography, cellular electrophysiology, intracellular Ca2+ imaging, and RNA-sequencing. The multiorgan HFpEF phenotype showed key differences between the 2 models, db/db+Aldo mice were markedly obese, had severe hyperglycaemia and hepatomegaly, whereas male HFD+L-NAME mice had more pronounced cardiac hypertrophy. Diastolic dysfunction was more severe in db/db+Aldo mice and worse in females therein, whereas female sex was protective in HFD+L-NAME. Marked proarrhythmic action potential (AP) changes (AP prolongation, increased short-term variability and alternans threshold) occurred in db/db+Aldo (in both sexes), these AP changes were less severe in male HFD+L-NAME and absent in female HFD+L-NAME. In line with these, differential ionic current and Ca2+ handling changes occurred between these two HFpEF models and between sexes in each model. RNA-sequencing revealed highly distinctive gene expression profiles between HFpEF models. We conclude that marked differences exist in cardiomyocyte ECC, electrophysiology, and gene expression between HFD+L-NAME and db/db+Aldo mice and between sexes. This indicates that a combination of translational HFpEF models that mimic select HFpEF sub-phenogroups are needed to better understand HFpEF mechanisms for therapeutic drug development.
2025-12-02 | GSE284354 | GEO
Project description:Aims: Despite the high prevalence of heart failure with preserved ejection fraction (HFpEF), the pathomechanisms remain elusive and specific therapy is lacking. Disease-causing factors include metabolic risk, notably obesity. However, proteomic changes in HFpEF are poorly understood, hampering therapeutic strategies. We sought to elucidate how metabolic syndrome affects cardiac protein expression, phosphorylation and acetylation in the Zucker diabetic fatty/Spontaneously hypertensive heart failure F1 (ZSF1) rat HFpEF model, and to evaluate some changes regarding their potential for treatment. Main methods: ZSF1 obese and lean rats were fed a Purina diet up to the onset of HFpEF in the obese animals. We quantified the proteome, phosphoproteome and acetylome of ZSF1 obese versus lean heart tissues by mass spectrometry and singled out targets for site-specific evaluation. Key findings: We found the acetylome of ZSF1 obese versus lean hearts more severely altered (21% of proteins changed) than the phosphoproteome (9%) or proteome (3%). Proteomic alterations, confirmed by immunoblotting, indicated low-grade systemic inflammation and endothelial remodeling in obese hearts, but low nitric oxide-dependent oxidative/nitrosative stress. Altered acetylation in ZSF1 obese hearts mainly affected pathways important for metabolism, energy production and mechanical function, including hypo-acetylation of mechanical proteins but hyper-acetylation of proteins regulating fatty acid metabolism. Hypo-acetylation and hypo-phosphorylation of elastic titin in ZSF1 obese hearts explained myocardial stiffening. Significance: Cardiometabolic syndrome alters posttranslational modifications, notably acetylation, in experimental HFpEF. Pathway changes implicate a HFpEF signature of low-grade inflammation, endothelial dysfunction, metabolic and mechanical impairment, and suggest titin stiffness and mitochondrial metabolism as promising therapeutic targets.
2022-10-12 | PXD036259 | Pride
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.
2024-03-05 | PXD045677 | Pride
Project description:Heart failure with preserved ejection fraction (HFpEF) accounts for half of heart failure cases and is characterised by reduced pericyte coverage. While the contributions of other cardiac cell types to HFpEF are well-studied, the role of pericytes remains less understood. Using murine single-nucleus RNA sequencing to study cardiac pericytes in HFpEF, we identified reduced STAT3 expression as a hallmark of HFpEF pericytes. Mechanistic studies in vitro revealed that STAT3 deletion induces cellular senescence and impairs pericyte adhesion, recapitulating HFpEF-like characteristics. These findings suggest that STAT3 is crucial for maintaining pericyte homeostasis and highlight its reduction as a potential driver of pericyte loss, a defining feature of HFpEF.
2025-04-25 | E-MTAB-15019 | biostudies-arrayexpress
Project description:Immune cell activation in heart failure is poorly understood. We profiled circulating leukocytes in humans with heart failure with preserved ejection fraction and non heart failure controls to identify novel changes associated with HFpEF diagnosis
2024-09-01 | GSE223527 | GEO
Project description:Effective treatments for heart failure with preserved ejection fraction (HFpEF) are limited. Empagliflozin, a sodium-glucosecotransporter-2 (SGLT2) inhibitor, provides cardiovascular benefits for patients with HFpEF. SGLT2 expression is virtually absent in cardiomyocytes, hence the exact protective mechanism of empagliflozin is unclear. We aimed to study the effect of in vivo empagliflozin treatment on excitationâcontraction coupling (ECC), electrophysiology, and gene transcription in a translational two-hit HFpEF mouse model that combines the obese-diabetic leptin receptor-deficient db/db mice with chronic aldosterone infusion (db/db + Aldo). We performed morphometry, echocardiography, cardiomyocyte electrophysiology, intracellular Ca imaging, and whole-heart RNA-sequencing in empagliflozin-treated db/db + Aldo and vehicle control mice. In db/db + Aldo mice, empagliflozin (in vivo, 4weeks) reduced the elevated plasma blood glucose (13 ± 5 mmol/L versus 23 ± 8 mmol/L) and BNP levels, prevented pulmonary congestion, and ameliorated diastolic dysfunction. However, empagliflozin did not reduce cardiac hypertrophy and obesity. In healthy control mice, empagliflozin had no functional effect. Chronic in vivo empagliflozin treatment in db/db + Aldo also normalized the changes in cardiomyocyte electrophysiology and Ca handling properties measured in the absence of empagliflozin in the perfusion solution during cell experiments, indicating a true phenotypic rescue. Differentially expressed gene clusters were identified characteristic of the db/db genotype, aldosterone, and empagliflozin treatments. Interestingly, empagliflozin did not just reverse the HFpEF-altered gene expression but shifted it further away from control to a new expression profile. We conclude that chronic in vivo empagliflozin treatment restores cardiomyocyte electrophysiological and ECC properties, ameliorates diastolic function in cardiometabolic HFpEF, and induces complex gene expression changes.
2026-05-13 | GSE285966 | GEO
Project description:<p>Heart failure with preserved ejection fraction (HFpEF) is a complex cardiometabolic disorder closely associated with systemic metabolic dysregulation. In this study, plasma samples were collected from C57BL/6J mice subjected to a high-fat dietâinduced HFpEF model, with or without intervention, and analyzed using untargeted metabolomics to characterize disease-associated metabolic alterations. This dataset aims to provide insights into plasma metabolic signatures and mechanisms underlying HFpEF.</p>
2026-01-16 | MTBLS13700 | MetaboLights
Project description:Clinical management of heart failure with preserved ejection fraction (HFpEF) is hindered by a lack of disease-modifying therapies capable of altering its distinct pathophysiology. Despite the widespread implementation of a âtwo-hitâ model of cardiometabolic HFpEF to inform precision therapy, which utilizes ad libitum high-fat and 0.5% N(Ï)-nitro-L-arginine methyl ester (HFD+L-NAME) diet, we observe that C57BL6/J mice exhibit less cardiac diastolic dysfunction in response to HFD+L-NAME. Genetic strain-specific single-nucleus transcriptomic analysis identified disease-relevant genes that enrich oxidative metabolic pathways within cardiomyocytes. Because C57BL/6J mice are known to harbor a loss-of-function mutation affecting the inner mitochondrial membrane protein nicotinamide nucleotide transhydrogenase (Nnt), we used an isogenic model of Nnt loss-of-function to determine whether intact NNT is necessary for the pathological cardiac manifestations of HFD+L-NAME. Twelve-week-old mice cross-bred to isolate wild-type (Nnt+/+) or loss-of-function (Nnt-/-) Nnt in the C57BL/6N background, were challenged with HFD+L-NAME for 9 weeks (n = 6-10). Nnt+/+ mice exhibited impaired ventricular diastolic relaxation and pathological remodeling, as assessed via E/eâ (42.8 vs. 21.5, P = 1.2e-10), E/A (2.3 vs 1.4, P = 4.1e-2), diastolic stiffness (0.09 vs 0.04 mmHg/ÎŒL, P = 5.1e-3), and myocardial fibrosis (P = 2.3e-2). Liquid chromatography and mass spectroscopy exposed a 40.0% reduction in NAD+ (P = 8.4e-3) and a 38.8% reduction in GSH:GSSG (P = 2.6e-2) among Nnt+/+ mice after HFD+L-NAME feeding. Using single-nucleus ligand-receptor analysis, we implicate fibroblast growth factor 1 (Fgf1) as a putative NNT-dependent mediator of cardiomyocyte-to-fibroblast signaling of myocardial fibrosis. Together, these findings underscore the pivotal role of mitochondrial dysfunction in HFpEF pathogenesis and position both NNT and Fgf1 as novel therapeutic targets.
2025-04-12 | GSE225557 | GEO