Single cell RNA sequencing for non-cardiomyocytes in healthy, adaptive hypertrophy, and heart failure hearts of C57BL/6JJcl mice.
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE293319 | GEO | 2025/09/24
REPOSITORIES: GEO
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Project description:This sstudy was designed to investigate the gene netweork regulated by valosin-containing protein (VCP), an ATPase-associated protein, whic acts as a novel regulator against the cardiac stress of pressure overload. We performed transcriptome analyses to compare cardiac-specific VCP overexpression transgenic (TG) mice and wild-type (WT) mice in a series of pathological models. The left ventricular (LV) tissues were collected from both WT and VCP TG mice at 2w post TAC and at 2w post sham operations. mRNA was extracted and sequenced to generate gene expression profiles. Multiple comparisons were performed between VCP TG and WT mice at two treatment conditions: sham and 2w post TAC. Our studies revealed novel molecular mechanisms by which VCP protects heart against pressure overload-induced cardiac hypertrophy and the transition to the heart failure.
2020-09-24 | GSE134085 | GEO
Project description:Compelling evidence suggests that mitochondrial dysfunction contributes to the pathogenesis of heart failure, including defects in the substrate oxidation, and the electron transport chain (ETC) and oxidative phosphorylation (OXPHOS). However, whether such changes occur early in the development of heart failure, and are potentially involved in the pathologic events that lead to cardiac dysfunction is unknown. To address this question, we conducted transcriptomic/metabolomics profiling in hearts of mice with two progressive stages of pressure overload-induced cardiac hypetrophy: i) cardiac hypertrophy with preserved ventricular function achieved via transverse aortic constriction for 4 weeks (TAC) and ii) decompensated cardiac hypertrophy or heart failure (HF) caused by combining 4 wk TAC with a small apical myocardial infarction. Transcriptomic analyses revealed, as shown previously, downregulated expression of genes involved in mitochondrial fatty acid oxidation in both TAC and HF hearts compared to sham-operated control hearts. Surprisingly, however, there were very few changes in expression of genes involved in other mitochondrial energy transduction pathways, ETC, or OXPHOS. Metabolomic analyses demonstrated significant alterations in pathway metabolite levels in HF (but not in TAC), including elevations in acylcarnitines, a subset of amino acids, and the lactate/pyruvate ratio. In contrast, the majority of organic acids were lower than controls. This metabolite profile suggests “bottlenecks” in the carbon substrate input to the TCA cycle. This transcriptomic/metabolomic profile was markedly different from that of mice PGC-1a/b deficiency in which a global downregulation of genes involved in mitochondrial ETC and OXPHOS was noted. In addition, the transcriptomic/metabolomic signatures of HF differed markedly from that of the exercise-trained mouse heart. We conclude that in contrast to current dogma, alterations in mitochondrial metabolism that occur early in the development of heart failure reflect largely post-transcriptional mechanisms resulting in impedance to substrate flux into the TCA cycle, reflected by alterations in the metabolome.
2014-10-01 | GSE56348 | GEO
Project description:Compelling evidence suggests that mitochondrial dysfunction contributes to the pathogenesis of heart failure, including defects in the substrate oxidation, and the electron transport chain (ETC) and oxidative phosphorylation (OXPHOS). However, whether such changes occur early in the development of heart failure, and are potentially involved in the pathologic events that lead to cardiac dysfunction is unknown. To address this question, we conducted transcriptomic/metabolomics profiling in hearts of mice with two progressive stages of pressure overload-induced cardiac hypetrophy: i) cardiac hypertrophy with preserved ventricular function achieved via transverse aortic constriction for 4 weeks (TAC) and ii) decompensated cardiac hypertrophy or heart failure (HF) caused by combining 4 wk TAC with a small apical myocardial infarction. Transcriptomic analyses revealed, as shown previously, downregulated expression of genes involved in mitochondrial fatty acid oxidation in both TAC and HF hearts compared to sham-operated control hearts. Surprisingly, however, there were very few changes in expression of genes involved in other mitochondrial energy transduction pathways, ETC, or OXPHOS. Metabolomic analyses demonstrated significant alterations in pathway metabolite levels in HF (but not in TAC), including elevations in acylcarnitines, a subset of amino acids, and the lactate/pyruvate ratio. In contrast, the majority of organic acids were lower than controls. This metabolite profile suggests “bottlenecks” in the carbon substrate input to the TCA cycle. This transcriptomic/metabolomic profile was markedly different from that of mice PGC-1a/b deficiency in which a global downregulation of genes involved in mitochondrial ETC and OXPHOS was noted. In addition, the transcriptomic/metabolomic signatures of HF differed markedly from that of the exercise-trained mouse heart. We conclude that in contrast to current dogma, alterations in mitochondrial metabolism that occur early in the development of heart failure reflect largely post-transcriptional mechanisms resulting in impedance to substrate flux into the TCA cycle, reflected by alterations in the metabolome. Microarray gene expression profiling was performed with bi-ventricle RNA isolated from (1) 3 month-old female C57Bl6/J mice with transverse aortic constriction (CH), vs sham-operated control (Sham-CH), (2) 3 month-old female C57Bl6/J mice with heart failure (HF), vs. sham-operated control (Sham-HF); (3) 2 month-old female C57Bl6/J mice with voluntary wheel training for 2 months (Run), vs. Sedentary control (Sed). Five biological replicates are included for each group.
2014-10-01 | E-GEOD-56348 | biostudies-arrayexpress
Project description:Here, we performed pathological cardiac hypertrophy transcriptome analyses by using heart tissue from Sham or TAC surgery to identify the charecteric in pathological cardiac hypertrophy. In addition, through combined analysis with the aging-associated transcriptome to identify the similarity and difference between heart ageing and pathological cardiac hypertrophy.
2025-01-29 | GSE203083 | GEO
Project description:Transcriptome analysis of RNA samples from whole heart Transverse aortic constriction (TAC) is a well-established method for studying the pathomechanisms of heart failure in animal models of cardiac hypertrophy. A number of studies have shown that the treatment of heart failure in this animal model of cardiac hypertrophy suggests that hypertrophy and fibrosis may be reversible. However, since TAC-release protocols that improve hemodynamics by releasing physical stenosis remain undefined, the histological characteristics and molecular biological regulatory mechanisms of the reversibility of cardiac hypertrophy and fibrosis are unknown. Therefore, this study aimed to establish a TAC release model and investigate the reversibility and plasticity mechanisms of myocardial hypertrophy, fibrosis, and angiogenesis. Four weeks post-TAC surgery, TAC release was conducted by cutting the aortic stenosis sutures. The TAC group exhibited severe myocardial hypertrophy, fibrosis, and increased angiogenesis, along with diastolic dysfunction. Conversely, the TAC-release group showed reduced hypertrophy and fibrosis, and improved diastolic function. Gene expression analysis highlighted Regulator of Calcineurin 1 as a key player in cardiac function and histological changes post-TAC release. Rcan1 knockdown exacerbated myocardial hypertrophy and fibrosis in the TAC-release group. This study sheds light on the functional, structural, and histological changes in the heart induced by TAC release and elucidates some of its regulatory mechanisms.
2024-07-09 | GSE270186 | GEO
Project description:Pathological cardiac hypertrophy was induced by pressure overload on the heart. We performed genome-wide exon array experiments with left ventricles of mice with 1 week and 4 week of transverse aortic constriction (TAC). The exon level analysis revealed widespread regulation of alternative splicing and alternative polyadenylation during hypertrophy. Exon and gene expression changes were examined in 1 week and 4 week TAC-operated hearts compared to sham-operated hearts. We used C57/BL6 wildtype mice, and their left ventricles were subject to surgery (each n=2).
2011-05-01 | E-GEOD-24242 | biostudies-arrayexpress
Project description:An initial cellular change in the pathogenesis of heart failure is cardiomyocyte hypertrophy, characterized by increased cell size, enhanced protein synthesis and reactivation of fetal genes. In addition to mechanical stresses, several neurohumoral factors have been identified as potent hypertrophic agents, including angiotensin II, endothelin, and catecholamines. We used microarrays to study the gene expression during cardiac hypertrophy. Balb/c mice (6-8w) were treated with TAC, ATII infusion, and myocardial infarction. TAC model: The transverse aorta (TAC) was constricted at the upper left sternal border by ligation with a 7-silk surgical thread and 27-gauge needle, which was removed thereafter. Sham-operated controls underwent an identical procedure without TAC. At 1 week and 1month after the procedure, LV was harvested. Ang II model.: Ang II was dissolved in 0.9% NaCl at concentrations sufficient to allow an infusion rate of 2.0 mg/kg/day, known to produce hypertension and cardiac hypertrophy. Control mice received a vehicle (saline) via an osmotic minipump. At 1 week after the procedure, LV was harvested. MI model: The proximal portion of the left coronary artery was ligated using an 8-0 nylon thread. Myocardial ischemia was confirmed by the discoloration of the heart and typical ECG changes. After 30 min occlusion, the left coronary artery was reperfused by loosening the ligature. In sham-operated mice (SHAM), the pericardium was opened, but the coronary artery was not ligated. At 1 day, 1week, and 1 month after the procedure, LV was harvested.
2011-12-31 | E-GEOD-26671 | biostudies-arrayexpress
Project description:Pathological cardiac hypertrophy was induced by pressure overload on the heart. We performed genome-wide exon array experiments with left ventricles of mice with 1 week and 4 week of transverse aortic constriction (TAC). The exon level analysis revealed widespread regulation of alternative splicing and alternative polyadenylation during hypertrophy.
2011-05-01 | GSE24242 | 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:The identification of key factors involved in pathological cardiac hypertrophy is crucial to exploring novel treatments for heart failure. In this study, we elucidated the role of Ubiquitin-specific protease 29 (USP29), a deubiquitinase, in pressure overload-induced cardiac hypertrophy. Genetic knockout of USP29 in mice significantly exacerbated TAC-induced heart hypertrophy, dysfunction, and fibrosis; whereas overexpression of USP29 in cardiomyocytes attenuated the hypertrophic response. Similarly, USP29 markedly alleviated PE-induced hypertrophy of primary neonatal rat cardiomyocytes. Mechanistically, the cardio-protective effects mediated by USP29 were attributed to its suppression of transforming growth factor β-activated kinase 1 (TAK1)-JNK/P38 signaling pathway activation. Collectively, our study suggests that targeting either USP29 or its interaction with TAK1 could represent an innovative therapeutic strategy for treating heart failure and cardiac hypertrophy.
2024-04-20 | GSE263965 | GEO