Upregulated FoxO1 promotes arrhythmogenesis in mice with heart failure and preserved ejection fraction [6 wks]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE240400 | GEO | 2024/11/17
REPOSITORIES: GEO
Similar Datasets
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:Phosphorylation of sarcomeric proteins has been implicated in heart failure with preserved ejection fraction (HFpEF); such changes may contribute to diastolic dysfunction by altering contractility, cardiac stiffness, Ca2+-sensitivity and mechanosensing. Treatment with cardiosphere-derived cells (CDCs) restores normal diastolic function, attenuates fibrosis and inflammation, and improves survival in a rat HFpEF model. Here, we quantified the phosphorylation changes that underlie HFpEF and those reversed by CDC therapy, with a focus on the sarcomeric subproteome.
2022-04-23 | PXD025555 | Pride
Project description:Inflammation, fibrosis and metabolic stress critically promote heart failure with preserved ejection fraction (HFpEF). Exposure to high-fat diet and nitric oxide synthase inhibitor N[w]-nitro-l-arginine methyl ester (L-NAME) recapitulate features of HFpEF in mice. To identify disease specific traits during adverse remodeling, we profiled interstitial cells in early murine HFpEF using single-cell RNAseq (scRNAseq). Diastolic dysfunction and perivascular fibrosis were accompanied by an activation of cardiac fibroblast and macrophage subsets. Integration of fibroblasts from HFpEF with two murine models for heart failure with reduced ejection fraction (HFrEF) identified a catalog of conserved fibroblast phenotypes across mouse models. Moreover, HFpEF specific characteristics included induced metabolic, hypoxic and inflammatory transcription factors and pathways, including enhanced expression of Angiopoietin-like 4 (Angptl4) next to basement membrane compounds, such as collagen IV (Col4a1). Fibroblast activation was further dissected into transcriptional and compositional shifts and thereby highly responsive cell states for each HF model were identified. In contrast to HFrEF, where myofibroblast and matrifibrocyte activation were crucial features, we found that these cell states played a subsidiary role in early HFpEF. These disease-specific fibroblast signatures were corroborated in human myocardial bulk transcriptomes. Furthermore, we identified a potential cross-talk between macrophages and fibroblasts via SPP1 and TNFɑ with estimated fibroblast target genes including Col4a1 and Angptl4. Treatment with recombinant ANGPTL4 ameliorated the murine HFpEF phenotype and diastolic dysfunction by reducing collagen IV deposition from fibroblasts in vivo and in vitro. In line, ANGPTL4, was elevated in plasma samples of HFpEF patients and particularly high levels associated with a preserved global longitudinal strain. Taken together, our study provides a comprehensive characterization of molecular fibroblast activation patterns in murine HFpEF, as well as the identification of Angiopoietin-like 4 as central mechanistic regulator with protective effects.
2024-08-28 | GSE275031 | 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:As part of genetic studies of heart failure in mice, we observed that heart mitochondrial DNA levels and function tend to be reduced in females as compared to males. We also observed that expression of genes encoding mitochondrial proteins were higher in males than females in human cohorts. Heart failure with preserved ejection fraction (HFpEF) exhibits a sex bias, being more common in women than men, and we hypothesized that mitochondrial sex differences might underlie this bias. We tested this in a panel of genetically diverse inbred strains of mice, termed the Hybrid Mouse Diversity Panel (HMDP). Indeed, we found that mitochondrial gene expression was highly correlated with diastolic function, a key trait in HFpEF. Consistent with this, studies of a “two-hit” mouse model of HFpEF confirmed that mitochondrial function differed between sexes and was strongly associated with a number of HFpEF traits. By integrating data from human heart failure and the mouse HMDP cohort, we identified the mitochondrial protein Acsl6 as a genetic determinant of diastolic function. We validated its role in HFpEF using adenoviral over-expression in the heart. We conclude that sex differences in mitochondrial function underlie, in part, the sex bias in diastolic function.
2022-01-31 | GSE194151 | GEO
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:Left ventricular (LV) diastolic dysfunction is a hallmark of Heart Failure with preserved Ejection Fraction (HFpEF), an escalating global health challenge. We demonstrated selective depletion of the oxidized form of nicotinamide adenine dinucleotide (NAD+) and the rate-limiting enzyme of the NAD+ biosynthetic salvage pathway, nicotinamide phosphoribosyltransferase (NAMPT), in human myocardium with LV diastolic dysfunction. We showed that NAD+ can be replenished in human myocardium with diastolic impairment ex vivo, despite reduced NAMPT expression. In a murine model of HFpEF [a combination exposure to high-fat diet (HFD) and L-NG-Nitro arginine methyl ester (L-NAME)], we compared the benefits of NAD+ precursor supplementation versus dietary intervention. We tested NAD+ repletion by nicotinamide riboside (NR) supplementation using two clinically-relevant strategies: 1) Prophylactic NR repletion before HFpEF onset, and 2) Therapeutic NR repletion after the development of HFpEF. We found that dietary intervention (replacement of HFD and L-NAME with healthy diet) restored myocardial insulin-dependent glucose uptake and glycolysis but did not rescue HFpEF. In contrast, both NAD+ repletion strategies prevented or rescued HFpEF, respectively, plausibly due to restoration of myocardial iron homeostasis, recoupling of glycolysis to the TCA cycle, and upregulation of antioxidant defense.
2024-08-09 | PXD033027 | Pride
Project description:Heart failure with preserved ejection fraction (HFpEF) is a prevalent health condition associated with high morbidity and mortality, but currently, there are few effective therapies. Our previous research showed that inhibiting histone deacetylase 6 (HDAC6) had a beneficial effect on a genetic cardiomyopathy model. The overlapping underlying mechanisms involving inflammation and metabolism between cardiomyopathy and HFpEF prompted us to explore the role of HDAC6 in HFpEF. The results showed that inhibiting HDAC6 with TYA-018 reversed preexisting cardiac hypertrophy and diastolic dysfunction, and improved lung congestion and exercise capacity in mouse models of HFpEF, including a newly developed model that combines moderate trans-aortic constriction and high-fat diet to mimic the systemic and cardiovascular features of human HFpEF. Moreover, mice with genetic Hdac6 deletion delayed the development of HFpEF and were resistant to the effects of TYA-018. The efficacy of TYA-018 was comparable to a SGLT2 inhibitor, and the combination showed increased effects. Mechanistically, TYA-018 restored expression of gene sets associated with hypertrophy, fibrosis, and mitochondrial energy production in heart tissue from HFpEF mice. TYA-018 also inhibited activation of human cardiac fibroblasts and increased mitochondrial respiratory capacity in induced pluripotent stem cell–derived cardiomyocytes. These findings support the direct role of HDAC6 on HFpEF pathophysiology in the heart and that inhibiting HDAC6 may be a promising approach to treating HFpEF.
2024-01-18 | GSE249412 | GEO
Project description:Heart failure with preserved ejection fraction (HFpEF) is a prevalent health condition associated with high morbidity and mortality, but currently, there are few effective therapies. Our previous research showed that inhibiting histone deacetylase 6 (HDAC6) had a beneficial effect on a genetic cardiomyopathy model. The overlapping underlying mechanisms involving inflammation and metabolism between cardiomyopathy and HFpEF prompted us to explore the role of HDAC6 in HFpEF. The results showed that inhibiting HDAC6 with TYA-018 reversed preexisting cardiac hypertrophy and diastolic dysfunction, and improved lung congestion and exercise capacity in mouse models of HFpEF, including a newly developed model that combines moderate trans-aortic constriction and high-fat diet to mimic the systemic and cardiovascular features of human HFpEF. Moreover, mice with genetic Hdac6 deletion delayed the development of HFpEF and were resistant to the effects of TYA-018. The efficacy of TYA-018 was comparable to a SGLT2 inhibitor, and the combination showed increased effects. Mechanistically, TYA-018 restored expression of gene sets associated with hypertrophy, fibrosis, and mitochondrial energy production in heart tissue from HFpEF mice. TYA-018 also inhibited activation of human cardiac fibroblasts and increased mitochondrial respiratory capacity in induced pluripotent stem cell–derived cardiomyocytes. These findings support the direct role of HDAC6 on HFpEF pathophysiology in the heart and that inhibiting HDAC6 may be a promising approach to treating HFpEF.
2024-01-17 | GSE249409 | GEO