Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA177420 | ENA |
REPOSITORIES: ENA
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Project description:We hypothesized that the estrogen-related receptor a (ERRa), which recruits PGC-1a to metabolic target genes in heart, exerts protective effects in the context of stressors known to cause heart failure. ERRa-/- mice subjected to left ventricular (LV) pressure overload developed signatures of heart failure including chamber dilatation and reduced LV fractional shortening. 31P-NMR studies revealed abnormal phosphocreatine depletion in ERRa-/- hearts subjected to hemodynamic stress, indicative of a defect in ATP reserve. Mitochondrial respiration studies demonstrated reduced maximal ATP synthesis rates in ERRa-/- hearts. Cardiac ERRa target genes involved in energy substrate oxidation, ATP synthesis, and phosphate transfer were downregulated in ERRa-/- mice at baseline or with pressure overload. These results demonstrate that ERRa, a potential therapeutic target, is indispensable for the adaptive bioenergetic response to hemodynamic stressors known to cause heart failure. Experiment Overall Design: Microarray analyses were performed with two samples each of ERRawt and ERRako to compare baseline changes in gene expression. Validation real-time PCR (n=7) was subsequently performed to characterize expression changes of gene targets identified in microarray and ChIP-chip studies in hearts of ERRa wt and KO mice at baseline and subjected to pressure overload stress.
2008-06-15 | E-GEOD-8106 | biostudies-arrayexpress
Project description:We hypothesized that the estrogen-related receptor a (ERRa), which recruits PGC-1a to metabolic target genes in heart, exerts protective effects in the context of stressors known to cause heart failure. ERRa-/- mice subjected to left ventricular (LV) pressure overload developed signatures of heart failure including chamber dilatation and reduced LV fractional shortening. 31P-NMR studies revealed abnormal phosphocreatine depletion in ERRa-/- hearts subjected to hemodynamic stress, indicative of a defect in ATP reserve. Mitochondrial respiration studies demonstrated reduced maximal ATP synthesis rates in ERRa-/- hearts. Cardiac ERRa target genes involved in energy substrate oxidation, ATP synthesis, and phosphate transfer were downregulated in ERRa-/- mice at baseline or with pressure overload. These results demonstrate that ERRa, a potential therapeutic target, is indispensable for the adaptive bioenergetic response to hemodynamic stressors known to cause heart failure. Keywords: Genetic modification, stress response
2007-10-16 | GSE8106 | GEO
Project description:The endogenous peptide Apelin is crucial for maintaining heart function in pressure overload and aging Experiment Overall Design: Heart samples from Apelin knockout mice with pressure overload and sham control together with the wild-type mice with pressure overload and sham were compared
2008-06-15 | E-GEOD-7781 | biostudies-arrayexpress
Project description:The rapidly growing family of coregulators of nuclear receptors includes coactivators that promote transcription and corepressors that harbor the opposing function. In recent years, coregulators have begun to emerge as important regulators of metabolic homeostasis, including the p160 Steroid Receptor Coactivator (SRC) family. Members of the SRC family have been ascribed important roles in control of gluconeogenesis in liver and fatty acid oxidation in skeletal muscle. To provide a deeper and more granular understanding of the metabolic impact of SRC family members, we have performed targeted metabolomics analysis of key metabolic byproducts of glucose, fatty acid, and amino acid metabolism in mice with global knockout of SRC-1, SRC-2, or SRC-3. We measured amino acids, acyl carnitines, and organic acids in five tissues with key metabolic functions (liver, heart, skeletal muscle, brain, plasma) isolated from SRC-1, -2, or -3 knockout mice and their wild-type littermates in the fed and fasted conditions, thereby unveiling unique metabolic functions of each SRC coactivator. Overall, we observed entire groups or subgroups of metabolites belonging to discrete metabolic pathways that were influenced in different tissues and/or feeding states due to ablation of individual SRC isoforms. Surprisingly, we identified very few metabolites that changed universally across the three SRC knockout models. These findings demonstrate that coactivator function has very limited redundancy even within the homologous SRC coactivator family. Furthermore, this work also demonstrates the use of metabolomics as a means for identifying novel metabolic regulatory functions of transcriptional coregulators.
2013-04-10 | MTBLS30 | MetaboLights
Project description:Cardiac hypertrophy is regulated by the zinc finger-containing DNA binding factors Gata4 and Gata6, both of which are required to mount a productive growth response of the adult heart. To determine if Gata4 and Gata6 are redundant or have non-overlapping roles, we performed cardiomyocyte-specific conditional gene deletions for Gata4 and Gata6 in conjunction with reciprocal replacement with a transgene encoding either Gata4 or Gata6, during the pressure overload response. We determined that Gata4 and Gata6 play a redundant and dosage-sensitive role in programming the hypertrophic growth response itself following pressure overload stimulation. However, non-redundant functions were identified as functional decompensation induced by either Gata4 or Gata6 deletion was not rescued by the reciprocal transgene, and only Gata4 heart-specific deletion produced a reduction in capillary density after pressure overload. Gene expression profiling from hearts of these gene-deleted mice showed both overlapping and unique transcriptional codes, with Gata4 exhibiting the strongest impact. These results indicate that Gata4 and Gata6 play a dosage-dependent and semi-redundant role in programming cardiac hypertrophy, but that each has a unique role in maintaining cardiac homeostasis and adaptation to injury that cannot be compensated by the other. Microarray-bassed gene expression profiling identified overlapping, distinct, and quantitatively/differentially regulated classes of Gata4 or Gata6 regulated genes. To determine if Gata4 and Gata6 are redundant or have non-overlapping roles in programming cardiac hypertrophic responses and adaptation to stress or injury, we performed cardiomyocyte-specific conditional gene deletions for Gata4 and Gata6 in conjunction with reciprocal replacement with a transgene encoding either Gata4 or Gata6, during the pressure overload response.
2014-01-01 | E-GEOD-52317 | biostudies-arrayexpress
Project description:To identify the role of mRNA on the mouse heart during pressure overload induced heart failure, we have employed high-throughput sequencing to detect mRNA expression. Samples were collected from the sham group and the pressure overload groups (2, 4 and 8 weeks after TAC), with 2 samples per group. The candidate mRNA that may affect the process of heart failure was screened by comparing the pressure overload groups and the sham group.
2022-03-30 | GSE182985 | GEO
Project description:To identify the role of circRNA on the mouse heart during pressure overload induced heart failure, we have employed circRNA microarray expression profiling as a discovery platform to detect circRNA expression. Samples were collected from the sham group and the pressure overload groups (2, 4 and 8 weeks after TAC), with 2 samples per group. The candidate circRNA that may affect the process of heart failure was screened by comparing the pressure overload groups and the sham group.
2022-03-30 | GSE182912 | GEO
Project description:Circumstantial evidence links the development of heart failure to perturbations in oxidative metabolism and corresponding shifts in post-translational modifications (PTMs) of mitochondrial proteins, including lysine acetylation (Kac). Nonetheless, direct evidence that acetyl-PTMs compromise mitochondrial performance remains sparse. Here, we used a respiratory diagnostics platform and serial assessment of cardiac phenotype to evaluate functional consequences of mitochondrial hyperacetylation caused by cardiac deficiency of carnitine acetyltransferase (CrAT) and sirtuin 3 (Sirt3); enzymes that oppose Kac by buffering the acetyl CoA pool and catalyzing lysine deacetylation, respectively. Although the dual knockout (DKO) manipulation raised the cardiac acetyl-lysine landscape well beyond that observed in response to Sirt3 deficiency or pathophysiological heart remodeling, bioenergetics of DKO mitochondria were remarkably normal. Moreover, DKO hearts were not more vulnerable to pressure overload-induced dysfunction resulting from chronic transaortic constriction. The findings challenge the premise that hyperacetylation per se threatens metabolic resilience by causing broad-ranging damage to mitochondrial proteins. See Davidson et. al. 2019 for further experimental details, reagents, and references.
2020-10-02 | PXD013935 | Pride
Project description:The expression of the small molecular weight heat shock protein (Hsp) H11 kinase/Hsp22 (Hsp22) is restricted to a limited number of tissues, including the heart and skeletal muscle, both in rodents and in humans. We generated a mouse knockout (KO) model, and investigated the role of Hsp22 in regulating cardiac hypertrophy in response to pressure overload. We compared gene expression profiles between WT and KO mice in basal condition and three days pressure overload after transverse aortic constriction (TAC). These data illustrated a novel mechanism of Hsp22-related gene expression in response to cardiac stress. We used microarray to examine differential gene expression by Hsp22 deletion at baseline and 3-day pressure overload. Left ventricles from wild type and Hsp22 knockout mice were selected from basal condition (each, n=3) and TAC surgery (each, n=4).
2010-12-31 | E-GEOD-24489 | biostudies-arrayexpress
Project description:Atherosclerosis and pressure overload are major risk factors for the development of heart failure in patients. Cardiac hypertrophy often precedes the development of heart failure. However, underlying mechanisms are incompletely understood. To investigate pathomechanisms underlying the transition from cardiac hypertrophy to heart failure we used experimental models of atherosclerosis- and pressure overload-induced cardiac hypertrophy and failure, i.e. apolipoprotein E (apoE)-deficient mice, which develop heart failure at an age of 18 months, and non-transgenic C57BL/6J (B6) mice with heart failure triggered by 6 months of pressure overload induced by abdominal aortic constriction (AAC). The development of heart failure was monitored by echocardiography, invasive hemodynamics and histology. The microarray gene expression study of cardiac genes was performed with heart tissue from failing hearts relative to hypertrophic and healthy heart tissue, respectively. The microarray study revealed that the onset of heart failure was accompanied by a strong up-regulation of cardiac lipid metabolism genes involved in fat synthesis, storage and oxidation. Microarray gene expression profiling was performed with heart tissue isolated from (i) 18 month-old apoE-deficient mice relative to age-matched non-transgenic C57BL/6J (B6) mice, (ii) 6 month-old apoE-deficient mice with 2 months of chronic pressure overload induced by abdominal aortic constriction (AAC) relative to sham-operated apoE-deficient mice and nontransgenic B6 mice, (iii) 10 month-old B6 mice with 6 months of AAC relative to sham-operated B6 mice, and (iv) 5 month-old B6 mice with 1 month of AAC relative to age-matched B6 mice.
2010-12-03 | E-GEOD-25765 | biostudies-arrayexpress