Mitochondrial NNT promotes diastolic dysfunction in cardiometabolic Heart Failure with Reduced Ejection Fraction (HFpEF)
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ABSTRACT:
PROVIDER: PRJNA936179 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23513887.fastq.gz | Fastqsanger.gz | |||
| SRR23513888.fastq.gz | Fastqsanger.gz | |||
| SRR23513889.fastq.gz | Fastqsanger.gz | |||
| SRR23513890.fastq.gz | Fastqsanger.gz | |||
| SRR23513891.fastq.gz | Fastqsanger.gz |
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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 “two-hit” model of cardiometabolic HFpEF to inform precision therapy, which utilizes ad libitum high-fat and 0.5% N(ω)-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/e’ (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/μL, 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
Project description:Heart failure with preserved ejection fraction (HFpEF) remains a major public health burden with increasing prevalence but only few effective therapies. Endothelial dysfunction and inflammation are identified as pathophysiological drivers of HFpEF disease progression. MicroRNAs are increasingly recognized as key regulators of these pathological processes, while antimiR-based therapies have been emerged as promising therapeutics in mice and humans. Therefore, we tested whether targeting miR-92a-3p inhibition is a promising therapeutic intervention to target HFpEF in vivo. By injection of locked nucleic acid (LNA)-based antimiR (LNA-92a) weekly, we demonstrate that inhibition of miR-92a-3p attenuates the development of diastolic dysfunction and left atrial dilation following experimental induction of HFpEF in mice. Indeed, LNA-92a depleted miR-92a-3p expression in the myocardium and peripheral blood, and derepressed predicted target genes in a cell type-specific manner. Furthermore, cell-type specific efficacy of LNA-92a treatment was assessed by single-nuclear RNA sequencing of HFpEF hearts either treated with LNA-92a or LNA-Control. Endothelial cells of LNA-92a treated mice showed normalized vascular gene expression and reduced gene signatures associated with endothelial-mesenchymal transition. Conclusion: This study demonstrates that LNA-based antimiR-92a is an effective therapeutic strategy to target diastolic dysfunction and left atrial dilation in HFpEF.
2024-11-21 | E-MTAB-14589 | biostudies-arrayexpress
Project description:Heart failure with preserved ejection fraction (HFpEF) is a highly prevalent and intractable form of cardiac decompensation commonly associated with diastolic dysfunction. Here, we show that diastolic dysfunction in patients with HFpEF is associated with a cardiac deficit in nicotinamide adenine dinucleotide (NAD+). Elevating NAD+ by oral supplementation of its precursor, nicotinamide, improved diastolic dysfunction induced by aging (in 2-year-old C57BL/6J mice), hypertension (in Dahl salt-sensitive rats) or cardiometabolic syndrome (in ZSF1 obese rats). Mechanistically, this effect was mediated partly through alleviated systemic comorbidities and enhanced myocardial bioenergetics, as evidenced by cardiac trasncriptome and metabolome analyses. Simultaneously, nicotinamide directly improved cardiomyocyte passive stiffness and calcium-dependent active relaxation through increased deacetylation of titin and the sarcoplasmic reticulum calcium ATPase 2a, respectively. In a long-term human cohort study, high dietary intake of naturally occurring NAD+ precursors was associated with lower blood pressure and reduced risk of cardiac mortality. Collectively, these results suggest NAD+ precursors, and especially nicotinamide, as potential therapeutic agents to treat diastolic dysfunction and HFpEF in humans.
2021-02-11 | GSE163665 | GEO
Project description:Myocardial fibrosis leads to cardiac dysfunction and arrhythmias in heart failure with preserved ejection fraction (HFpEF), but the underlying mechanisms remain poorly understood. Here, RNA sequencing identifies Forkhead Box1 (FoxO1) signaling as abnormal in HFpEF hearts. Genetic suppression of FoxO1 alters the intercellular communication between cardiomyocytes and fibroblasts, alleviates abnormal diastolic relaxation, and reduces arrhythmias. Targeted downregulation of FoxO1 in activated fibroblasts reduces cardiac fibrosis, blunts arrhythmogenesis and improves diastolic function in HFpEF. These results not only implicate FoxO1 in arrhythmogenesis and lusitropy but also demonstrate that pro-fibrotic cardiomyocyte-fibroblast communication can be corrected, constituting a novel therapeutic strategy for HFpEF.
2024-11-17 | GSE240400 | GEO
Project description:Myocardial fibrosis leads to cardiac dysfunction and arrhythmias in heart failure with preserved ejection fraction (HFpEF), but the underlying mechanisms remain poorly understood. Here, RNA sequencing identifies Forkhead Box1 (FoxO1) signaling as abnormal in HFpEF hearts. Genetic suppression of FoxO1 alters the intercellular communication between cardiomyocytes and fibroblasts, alleviates abnormal diastolic relaxation, and reduces arrhythmias. Targeted downregulation of FoxO1 in activated fibroblasts reduces cardiac fibrosis, blunts arrhythmogenesis and improves diastolic function in HFpEF. These results not only implicate FoxO1 in arrhythmogenesis and lusitropy but also demonstrate that pro-fibrotic cardiomyocyte-fibroblast communication can be corrected, constituting a novel therapeutic strategy for HFpEF.
2024-11-17 | GSE240403 | GEO
Project description:Myocardial fibrosis leads to cardiac dysfunction and arrhythmias in heart failure with preserved ejection fraction (HFpEF), but the underlying mechanisms remain poorly understood. Here, RNA sequencing identifies Forkhead Box1 (FoxO1) signaling as abnormal in HFpEF hearts. Genetic suppression of FoxO1 alters the intercellular communication between cardiomyocytes and fibroblasts, alleviates abnormal diastolic relaxation, and reduces arrhythmias. Targeted downregulation of FoxO1 in activated fibroblasts reduces cardiac fibrosis, blunts arrhythmogenesis and improves diastolic function in HFpEF. These results not only implicate FoxO1 in arrhythmogenesis and lusitropy but also demonstrate that pro-fibrotic cardiomyocyte-fibroblast communication can be corrected, constituting a novel therapeutic strategy for HFpEF.
2024-11-17 | GSE240401 | GEO
Project description:Although the prevalence of heart failure with preserved ejection fraction (HFpEF) is increasing, evidence-based therapies for HFpEF are rare, likely due to an incomplete understanding of this disease. This study sought to identify the cardiac-specific features of protein and phosphoprotein in a murine model of HFpEF using mass spectrometry. HFpEF mice developed moderate hypertension, left ventricle (LV) hypertrophy, lung congestion and diastolic dysfunction. Proteomics analysis of the LV tissue showed that 897 proteins were differentially expressed between HFpEF and Sham mice. We observed abundant changes in sarcomeric proteins, mitochondrial-related proteins, and NAD-dependent protein deacetylase sirtuin-3 (SIRT3). Upregulated pathways by GSEA analysis were related to immune modulation and muscle contraction, while downregulated pathways were predominantly related mitochondrial metabolism. Western blot analysis validated SIRT3 downregulated cardiac expression in HFpEF. Phosphoproteomics analysis showed that 72 phosphopeptides were differentially regulated between HFpEF and sham LV. Aberrant phosphorylation patterns mostly occurred in sarcomere proteins and nuclear-localized proteins associated with contractile dysfunction and cardiac hypertrophy. Seven aberrant phospho-sites were observed at the z disk binding region of titin. While total titin cardiac expression remained unaltered, its stiffer N2B isoform was significantly increased in HFpEF. Thus, these results show profound changes in proteins related to mitochondrial metabolism and function and the cardiac contractile apparatus in HFpEF. We propose that SIRT3 plays a key role and may be a target for drug development in HFpEF.
2022-10-15 | PXD033501 | Pride
Project description:Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome with multisystem organ dysfunction in which patients develop symptoms of HF as the result of high left ventricular (LV) diastolic pressure Continuous infusion of angiotensin II and phenylephrine (AngII/PE) demonstrates a strong HFpEF phenotype RNAseq data demonstrate activation of pathways leading to myocardial metabolic changes, activation of ECM deposition, microvascular rarefaction, and pressure and volume related myocardial stress
2023-06-07 | GSE221502 | GEO
Project description:Background: Despite the high morbidity and mortality of heart failure with preserved ejection fraction (HFpEF), treatment options remain limited. The HFpEF syndrome is associated with a high comorbidity burden, including high prevalence of obesity and hypertension. While inflammation is implicated to play a key role in HFpEF pathophysiology, underlying causal mechanisms remain unclear. Methods: Comparing patient samples and animal models, we defined the innate immune response during HFpEF in situ and through flow cytometry, and single cell RNA sequencing. After identification of transcriptional and cell signatures, we implemented a high fat diet and hypertensive model of HFpEF and tested roles for myeloid and hematopoietic stem cells (HSCs) during HFpEF. Contributions of macrophage metabolism were also evaluated, including via mass spectrometry and carbon labelling. Primary macrophages were studied ex vivo to gain insight into complementary cell- intrinsic mechanisms. Results: Here we report evidence that patients with cardiometabolic HFpEF exhibit elevated peripheral blood hematopoietic stem cells (HSCs). This phenotype was conserved across species in a murine mode of high fat diet and hypertension. HSC proliferation was coupled to striking remodeling of the peripheral HSC niche, and expression of the macrophage adhesion molecule Vcam1. This could be partially inhibited by SGLT2 inhibitors and explained by elevated fatty acid metabolism in macrophage mitochondria, which in turn remodeled the Vcam1 promoter to enhance its expression. Conclusion: These findings identify a significant new stem cell signature of cardiometabolic HFpEF and support a role for myeloid maladaptive fatty acid metabolism in the promotion of systemic inflammation and cardiac diastolic dysfunction.
2025-03-20 | GSE288048 | 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