Mus musculus
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ABSTRACT:
PROVIDER: PRJNA285288 | ENA |
REPOSITORIES: ENA
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Project description:Cardiac-specific Glut1 transgenic (Glut1-TG) mice exhibited higher glucose uptake and utilization compared with wild type mice. Cardiac pathological hypertrophy is accompanied by a switch of substrate metabolism from fatty acid oxidation to glucose use, resulting in a fetal like metabolic profile. However, the role of increasing glucose utilization in regulating cardiomyocyte growth is poorly understood. In order to identify novel pathways that is regulated by glucose, we performed microarray analyses using hearts from Glut1-TG and WT mice. The microarray analyses revealed that many genes that are involved in branched-chain amino acids (BCAAs) were downregulated in Glut1-TG mice.
2018-05-14 | GSE110766 | GEO
Project description:Rationale: Estrogens attenuate cardiac hypertrophy and increase cardiac contractility via their cognate receptors ERα and ERβ. Since female sex hormones enhance global glucose utilization and because myocardial function and mass are tightly linked to cardiac glucose metabolism we tested the hypothesis that expression and activation of the estrogen receptor α (ERα) might be required and sufficient to maintain physiological cardiac glucose uptake in the murine heart. Methods and Results: Cardiac glucose uptake quantified in vivo by 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) was strongly impaired in ovarectomized compared to gonadal intact female C57BL/6JO mice. The selective ERα agonist 16α-LE2 and the non-selective ERα and ERβ agonist 17β-estradiol completely restored cardiac glucose uptake in ovarectomized mice. Cardiac FDG uptake was strongly decreased in female ERα knockout mice (ERKO) compared to wild type littermates. Biochemical assays, affymetrix cDNA array analysis, western blotting and immuno-staining of cardiac glucose transporters revealed a positive correlation of ERα dependent cardiac FDG uptake with preserved cardiac glucose transporter-1 expression and micro-vascular localization. Conclusions: Systemic activation of the ERα estrogen receptor is sufficient and its expression is required to maintain physiological glucose uptake in the murine heart, which is likely to contribute to known cardio-protective estrogen effects. total samples analysed are 20
2012-12-20 | E-GEOD-34807 | biostudies-arrayexpress
Project description:Rationale: Estrogens attenuate cardiac hypertrophy and increase cardiac contractility via their cognate receptors ERα and ERβ. Since female sex hormones enhance global glucose utilization and because myocardial function and mass are tightly linked to cardiac glucose metabolism we tested the hypothesis that expression and activation of the estrogen receptor α (ERα) might be required and sufficient to maintain physiological cardiac glucose uptake in the murine heart. Methods and Results: Cardiac glucose uptake quantified in vivo by 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) was strongly impaired in ovarectomized compared to gonadal intact female C57BL/6JO mice. The selective ERα agonist 16α-LE2 and the non-selective ERα and ERβ agonist 17β-estradiol completely restored cardiac glucose uptake in ovarectomized mice. Cardiac FDG uptake was strongly decreased in female ERα knockout mice (ERKO) compared to wild type littermates. Biochemical assays, affymetrix cDNA array analysis, western blotting and immuno-staining of cardiac glucose transporters revealed a positive correlation of ERα dependent cardiac FDG uptake with preserved cardiac glucose transporter-1 expression and micro-vascular localization. Conclusions: Systemic activation of the ERα estrogen receptor is sufficient and its expression is required to maintain physiological glucose uptake in the murine heart, which is likely to contribute to known cardio-protective estrogen effects.
2012-12-20 | GSE34807 | GEO
Project description:Background Pathological cardiac hypertrophy remains a major contributor to heart failure, with impaired glucose metabolism playing a central role. Although exercise is known to enhance myocardial glucose utilization, the long-term metabolic reprogramming effects of exercise and their role in preventing pathological hypertrophy are poorly understood. This study elucidates the mechanisms underlying the sustained metabolic memory induced by exercise hypertrophic preconditioning (EHP) and its cardioprotective effects, with a focus on RNA methylation and arachidonic acid metabolism. Methods We employed PET/CT to assess cardiac glucose uptake and bulk RNA sequencing to profile myocardial gene expression in sedentary (Sed) and EHP mice. Genetic manipulation of Pdk4 was achieved via adeno-associated virus mediated overexpression and tamoxifen-inducible, cardiac-specific knockout (Pdk4-CKO). Pressure overload was induced by transverse aortic constriction (TAC) in Pdk4-CKO and control (Myh6-CreER, MCM) mice. Epigenetic regulation of Pdk4 by EHP was investigated using pyrosequencing, SELECT-qPCR and dual-luciferase assays. Untargeted metabolomics and molecular docking, molecular dynamics simulation, and CETSA were performed on heart tissues and neonatal rat cardiomyocytes/fibroblasts to identify key metabolites and their mechanisms of action. Results: EHP conferred sustained myocardial glucose preference even after regression of physiological hypertrophy, mediated through METTL3-dependent m6A RNA methylation that suppressed Pdk4 expression. Pdk4 overexpression abolished EHP-mediated cardioprotection, whereas Pdk4 deletion enhanced cardiac function and attenuated fibrosis under pressure overload. Metabolomic profiling identified arachidonic acid-derived metabolites 5-KETE, 12-keto-leukotriene B4, and 20-hydroxy-leukotriene B4 as novel inhibitors of hypertrophy and fibrosis. These metabolites attenuated cardiomyocyte hypertrophy and fibroblast trans-differentiation through inhibition of the ERK2/MAPK1 pathway. Conclusions: This study establishes a unified mechanism by which EHP induces metabolic memory through RNA methylation-dependent suppression of Pdk4, leading to altered arachidonic acid metabolism and the accumulation of protective lipid mediators. These findings highlight the therapeutic potential of targeting the PDK4–arachidonic acid metabolites axis to mitigate pathological cardiac remodeling.
2026-04-18 | GSE315915 | GEO
Project description:An important event in the pathogenesis of heart failure is the development of pathological cardiac hypertrophy. In cultured cardiac cardiomyocytes, the transcription factor Gata4 is required for agonist-induced cardiomyocyte hypertrophy. We hypothesized that in the intact organism Gata4 is an important regulator of postnatal heart function and of the hypertrophic response of the heart to pathological stress. To test this hypothesis, we studied mice heterozygous for deletion of the second exon of Gata4 (G4D). At baseline, G4D mice had mild systolic and diastolic dysfunction associated with reduced heart weight and decreased cardiomyocyte number. After transverse aortic constriction (TAC), G4D mice developed overt heart failure and eccentric cardiac hypertrophy, associated with significantly increased fibrosis and cardiomyocyte apoptosis. Inhibition of apoptosis by overexpression of the insulin-like growth factor 1 receptor prevented TAC-induced heart failure in G4D mice. Unlike WT-TAC controls, G4D-TAC cardiomyocytes hypertrophied by increasing in length more than width. Gene expression profiling revealed upregulation of genes associated with apoptosis and fibrosis, including members of the TGF? pathway. Our data demonstrate that Gata4 is essential for cardiac function in the postnatal heart. After pressure overload, Gata4 regulates the pattern of cardiomyocyte hypertrophy and protects the heart from load-induced failure. Experiment Overall Design: We reasoned that if Gata4 was a crucial regulator of pathways necessary for cardiac hypertrophy, then modest reductions of Gata4 activity should result in an observable cardiac phenotype. To test this hypothesis, we used gene targeted mice that express reduced levels of Gata4. We characterized these mice at baseline and after pressure Experiment Overall Design: overload.
2007-11-13 | E-GEOD-5500 | biostudies-arrayexpress
Project description:Hypertrophic cardiomyopathy (HCM) is one of the most frequent inherited heart condition and a well-established risk factor for cardiovascular mortality worldwide. Although hypertrophy is traditionally regarded as an adaptive response to increased workload caused by physiological or pathological stress, prolonged hypertrophy can lead to heart failure characterized by impaired systolic function, increased apoptosis, fibrosis, ventricular dilation, and impaired metabolic substrate flexibility. While the key regulators for cardiac hypertrophy are well studied, the role of Prdm16 in this process remains poorly understood. In the present study, we demonstrate that Prdm16 is dispensable for cardiac development. However, it is required in the adult heart to preserve mitochondrial function and inhibit hypertrophy with advanced age. Cardiac-specific deletion of Prdm16 results in cardiac hypertrophy, excessive ventricular fibrosis, mitochondrial dysfunction, and impaired metabolic flexibility, leading to heart failure. We demonstrate that Prdm16 and euchromatic histone-lysine N- methyltransferase factors (Ehmts) act together to reduce the expression of fetal genes reactivated in pathological hypertrophy by inhibiting the functions of pro- hypertrophic transcription factor Myc. Although young Prdm16 knockout mice show normal cardiac function, they are predisposed to develop heart failure in response to metabolic stress. Collectively, our results demonstrate that Prdm16 protects the heart against age-dependent cardiac hypertrophy, fibrosis, mitochondrial dysfunction, adverse metabolic remodeling, and heart failure.
2020-09-21 | GSE153988 | GEO
Project description:Transient Elevation in Cellular Glucose Uptake Exacerbates Pressure-Overload Induced Cardiac Hypertrophy and Dysfunction
| PRJNA1149838 | ENA
Project description:Kinase-catalyzed phosphorylation plays crucial roles in numerous biological processes. CDC-like kinases (CLKs) are a group of evolutionarily conserved dual-specificity kinases that have been implicated in RNA splicing, glucose metabolism, diet-induced thermogenesis and so on. However, it is still largely unknown whether CLKs are involved in pathologic cardiac hypertrophy. This study aimed to investigate the role of CLKs in pathologic cardiac hypertrophy and the underlying mechanisms. Using small RNA interference, we discovered that defects in CLK4, but not CLK1, CLK2 or CLK3, were associated with the pathogenesis of pathological cardiomyocyte hypertrophy, while overexpression of CLK4 exerted resistance to isoproterenol-induced pathological cardiomyocyte hypertrophy. Moreover, the expression of CLK4 was significantly reduced in the failed myocardia of mice subjected to either transverse aortic constriction or isoproterenol infusion. Through the Cre/loxP system, we constructed cardiac-specific Clk4-knockout (Clk4-cKO) mice, which manifested pathological myocardial hypertrophy with progressive left ventricular systolic dysfunction and heart dilation. Phosphoproteomic analysis revealed significant changes in phosphorylation of sarcomere-related proteins in Clk4-cKO mice. Further experiments identified nexilin (NEXN), an F-actin binding protein, as the direct substrate of CLK4, and overexpression of a phosphorylation-mimic mutant of NEXN was sufficient to reverse the hypertrophic growth of cardiomyocytes induced by Clk4 knockdown. Importantly, restoring the phosphorylated NEXN significantly ameliorated the myocardial hypertrophy in Clk4-cKO mice. CLK4 phosphorylates NEXN to regulate the development of pathological cardiac hypertrophy. CLK4 may serve as a potential intervention target for the prevention and treatment of heart failure.
2022-07-05 | PXD029682 | Pride
Project description:We show that an excess of VEGF-B protects the heart via adaptive cardiac hypertrophy and increased coronary arterial reserve, and by inducing a shift from lipid to glucose metabolism. Six VEGF-B overexpressing transgenic hearts were compared to six littermate wildtype controls
2013-11-30 | E-GEOD-38454 | biostudies-arrayexpress