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:Cardiac macrophages (cMacs) elimination exacerbates pressure overload-induced heart failure. However, the role of functionally distinct subsets of cMacs in heart failure remains largely unknown. CD163, a macrophage-specific scavenger receptor expressed in a subset of cMacs, has been associated with cardiovascular events through its circulating soluble form. This study aimed to elucidate the functional role of the CD163+ cMacs subset in pressure overload-induced heart failure. Transverse aortic constriction (TAC) was used to induce pressure overload. TAC-induced left ventricular systolic dysfunction, characterized by reduced ejection fraction and fractional shortening, was significantly aggravated in Cd163−/− mice post-surgery. Genes differentially expressed due to CD163 deficiency were enriched in pathways related to mitochondrial bioenergetics and homeostasis. Transmission electron microscopy revealed an increase in dysfunctional mitochondria in cardiomyocytes of Cd163−/− mice post-TAC. Additionally, decreased serum interleukin (IL)-10 levels and reduced IL-10 expression in cMacs were observed in Cd163−/− mice post-TAC. IL-10 supplementation significantly reversed TAC-induced reductions in left ventricular systolic function in Cd163−/− mice and improved mitochondrial functions in cardiomyocytes. Furthermore, decreased IL-10 levels and increased soluble CD163 were identified as risk factors for heart failure in hypertensive patients. Thus, CD163 in cMacs attenuates pressure overload-induced left ventricular systolic dysfunction through IL-10.
2025-05-08 | GSE223346 | GEO
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:Background Chronic sustained pressure overload induces cardiac remodeling, which often leads to heart failure. Cardiac macrophages (cMacs) are heterogeneous cell populations, and their elimination has been shown to exacerbate pressure overload-induced heart failure. CD163, a macrophage-specific scavenger receptor expressed in a subset of cMacs, has been linked to cardiovascular events through its serum soluble form. This study aimed to elucidate the functional role of the CD163+ cMacs subset in pressure overload-induced heart failure. Methods Transverse aortic constriction (TAC) was performed on wild-type and CD163-deficient (Cd163-/-) mice to investigate the role of CD163 in pressure overload-induced cardiac remodeling and heart failure. Echocardiography was used to assess heart structure and function. Transcriptomic analysis and transmission electron microscopy were employed to observe mitochondrial structure in cardiomyocytes. Flow cytometry was used to quantify cMacs and cytokine-expressing cMacs in the heart. Additionally, serum samples from hypertensive patients with and without heart failure were analyzed to explore the relationship between CD163 and heart failure. Results TAC-induced left ventricular systolic dysfunction, including reduced ejection fraction and fractional shortening, was significantly aggravated in Cd163-/- mice post-surgery. Genes differentially expressed due to CD163 deficiency were enriched in pathways related to mitochondrial bioenergetics and homeostasis. Transmission electron microscopy revealed an increase in dysfunctional mitochondria in cardiomyocytes of Cd163-/- mice post-TAC. Additionally, decreased serum interleukin (IL)-10 levels and reduced IL-10 expression in cMacs were observed in Cd163-/- mice post-TAC. IL-10 supplementation significantly reversed TAC-induced reductions in left ventricular systolic function and improved mitochondrial bioenergetics and homeostasis in Cd163-/- mice. Conclusions The protective functions of CD163 in cMacs are associated with IL-10 expression during pressure overload-induced heart failure.
2025-05-08 | GSE277624 | GEO
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