Cardiopulmonary Phenotyping of Sex-Based Differences in a Feline Model of HFpEF
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PROVIDER: PRJNA764081 | ENA |
REPOSITORIES: ENA
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Project description:In order to better understand sex-related differences of heart failure with preserved ejection fraction (HFpEF), male and female kittens underwent aortic contriction surgery (banding) or sham surgery (normal). Slow progressive pressure overload was then compared between male and female kittens, analyzing structural and functional phenotypes. Transcriptional differences between male and female kittens were investigated via single nuclear RNA sequencing (snRNA-seq) within left ventricle tissue.
2022-09-16 | GSE184328 | GEO
Project description:Heart Failure with preserved Ejection Fraction (HFpEF) is a major global health problem but there are no effective therapies. The aim of this study was to assess the effects of histone deacetylase (HDAC) inhibition on cardiopulmonary structure, function, and metabolism in a large mammalian (feline) pressure overload model with HFpEF features. Male domestic short hair cats (n=26, aged 2mo), underwent either a sham procedure (n=5) or aortic constriction (n=21) using a pre-shaped band, resulting in slow-progressive pressure overload during subsequent growth. Two-months post-banding, banded cats were treated daily with either 10mg/kg suberoylanilide hydroxamic acid (b+SAHA) (n=8), an FDA approved pan-HDAC inhibitor, or vehicle (b+veh) (n=8) for 2 months. Echocardiography at 4-months post-banding revealed that b+SAHA animals had a significant reduction in left ventricular hypertrophy (LVH) and LA size vs b+veh animals. Invasively measured left ventricular end-diastolic pressure (LVEDP) and mean pulmonary arterial pressure (mPAP) were significantly elevated in b+veh and significantly reduced by b+SAHA. SAHA speeded ex-vivo myofibril relaxation independent of LVH and this effect correlated with in-vivo indices of LV relaxation. Furthermore, SAHA preserved lung structure, improved lung compliance and oxygenation, reflected by a decrease in alveolar-capillary wall thickness, alveolar-arterial oxygen gradient (A-aDO2), and intrapulmonary shunt. SAHA also reduced perivascular fluid cuffs around extra-alveolar vessels, suggesting attenuated alveolar-capillary stress failure. Acetylation proteomics revealed that SAHA altered protein acetylation in cat hearts, including histones, many mitochondrial metabolic enzymes involved in electron transport chain, TCA cycle, malate aspartate shuttle and beta oxidation, as well as cytoskeletal proteins important for muscle function. These results suggest that acetylation defects in hypertrophic stress states can be reversed by HDAC inhibitors and may be useful to improve cardiac structure and function in HFpEF patients.
2021-09-08 | PXD013663 | Pride
Project description:Aims: Skeletal muscle (SkM) abnormalities may impact exercise capacity in patients with Heart Failure with Preserved Ejection Fraction (HFpEF). We sought to quantify differences in SkM oxidative phosphorylation capacity (OxPhos), fiber composition, and the SkM proteome between HFpEF, hypertensive (HTN), and Healthy participants. Methods: 59 subjects (20 Healthy, 19 HTN, 20 HFpEF) performed a maximal-effort cardiopulmonary exercise test to define peak oxygen consumption (VO2, peak), ventilatory threshold (VT), and VO2 efficiency (ratio of total work performed to O2 consumed). SkM OxPhos was assessed using Creatine Chemical-Exchange Saturation Transfer (CrCEST, n=51), which quantifies unphosphorylated Cr, before and after plantar flexion exercise. The half-time of Cr recovery (t1/2, Cr) was taken as a metric of in vivo SkM OxPhos. In a subset of subjects (Healthy=13, HTN=9, HFpEF=12), percutaneous biopsy of the vastus lateralis was performed for myofiber typing, mitochondrial morphology, and proteomic and phosphoproteomic analysis. Results: HFpEF subjects demonstrated lower VO2,peak, VT, and VO2 efficiency than either control group (all p<0.05). The t1/2, Cr was significantly longer in HFpEF (p=0.005), indicative of impaired SkM OxPhos, and correlated with cycle ergometry exercise parameters. HFpEF SkM contained fewer Type-I myofibers (p=0.003). Proteomic analyses demonstrated (a) reduced levels of proteins related to OxPhos that correlated with exercise capacity and (b) reduced ERK signaling in HFpEF. Conclusions: HFpEF patients demonstrate impaired functional capacity and SkM OxPhos. Reductions in the proportions of type 1 myofibers, proteins required for OxPhos, and altered phosphorylation signaling in the SkM may contribute to exercise intolerance in HFpEF.
2021-03-30 | PXD025092 | Pride
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:The purpose of this study was to characterize the transcriptomic alterations accompanying the inflammation involved in feline chronic gingivostomatitis (FCGS). Towards this goal next-generation sequencing (NGS)-based gene expression profiling (RNA-Sequencing; RNA-Seq) was performed on matched pairs of FCGS diseased and healthy tissues obtained from three feline subjects.
2020-09-25 | GSE149881 | 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.
2024-03-05 | PXD045677 | Pride
Project description:DEG and microRNA signatures from HFpEF ventricular biopsies.
| PRJEB62450 | ENA
Project description:In this study the authors used systems biology to define progressive changes in metabolism and transcription in a large animal model of heart failure with preserved ejection fraction (HFpEF). Transcriptomic analysis of cardiac tissue, 1 month post-banding, revealed loss of electron transport chain components, and this was supported by changes in metabolism and mitochondrial function, altogether signifying alterations in oxidative metabolism. Established HFpEF, 4 months post-banding, resulted in changes in intermediary metabolism with normalized mitochondrial function. Mitochondrial dysfunction and energetic deficiencies were noted in skeletal muscle at early and late phases of disease, suggesting cardiac-derived signaling contributes to peripheral tissue maladaptation in HFpEF. Collectively, these results provide insights into the cellular biology underlying HFpEF progression.
2021-09-01 | GSE181184 | GEO
Project description:This study looks at the effect of dietary manipulation on the development of hepatic steatosis and changes in hepatic gene expression in a feline model. We used microarray analysis to examine changes in hepatic gene transcription in response to Trans fat, High Fructose Corn Syrup (HFCS) and/or Monosodium Glutamate (MSG) in the domestic cat. The use of human Affymetrix arrays for the study of feline gene expression has previously been validated by Dowling and Bienzle, 2005, Journal of General Virology. 86(Pt 8), 2239-48 (PMID 16033971).
2014-06-11 | GSE30040 | GEO