Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA407337 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6038680.fastq.gz | Fastqsanger.gz | |||
| SRR6038690.fastq.gz | Fastqsanger.gz | |||
| SRR6038681.fastq.gz | Fastqsanger.gz | |||
| SRR6038691.fastq.gz | Fastqsanger.gz | |||
| SRR6038682.fastq.gz | Fastqsanger.gz |
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Project description:Metabolic and Transcriptional Alterations in the Early Stages of Cardiac Fuel Switch Hint at Novel mTOR-mediated Regulation of Hypertrophy
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Project description:Metabolic and Transcriptional Alterations in the Early Stages of Cardiac Fuel Switch Hint at Novel mTOR-mediated Regulation of Hypertrophy [Agilent Expression]
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Project description:1. Background- Long-chain acyl-CoA synthetases (ACSL) catalyze the conversion of long-chain fatty acids (FA) to fatty acyl-CoAs. Cardiac-specific ACSL1 knockout results in a shift towards glycolysis that promotes mTORC1-mediated ventricular hypertrophy. We used unbiased metabolomics and gene expression analyses to examine the early effects of genetic inactivation of FA oxidation on cardiac metabolism and function. 2. Methods and Results- Compared to WT hearts, global cardiac transcriptional analysis revealed differential expression of 245 genes in Acsl1H-/- hearts 2 weeks after Acsl1 ablation. Comparison of the 2- and 10-week transcriptional responses uncovered 139 genes whose expression was uniquely changed upon short-term cardiac inactivation of ACSL1. In particular, partial ACSL1 ablation led to the distinct upregulation of fibrosis genes, a phenomenon not observed after complete ACSL1 knockout. Metabolomic analysis identified 65 metabolites altered in hearts displaying partially reduced ACSL activity, whereas rapamycin treatment normalized the cardiac metabolomic fingerprint. Chronic mTOR inhibition via rapamycin treatment revealed novel mTORC1 targets involved in fibrosis, amino acid catabolism, and mitochondrial transport and metabolism. 3. Conclusions- Short-term cardiac-specific ACSL1 inactivation (Acsl1H-/-) resulted in metabolic and transcriptional derangements distinct from those observed upon complete ACSL1 knockout, leading to the identification of novel mTORC1 targets that regulate cardiac hypertrophy development, and suggesting heart-specific mTOR signaling that occurs during the early stages of substrate switching. Moreover, the rate of increased glucose use correlated negatively with hypertrophy development, strongly suggesting that hearts do not become hypertrophied if they can compensate or switch faster from FA to glucose use.
2018-04-27 | GSE103376 | GEO
Project description:1. Background- Long-chain acyl-CoA synthetases (ACSL) catalyze the conversion of long-chain fatty acids (FA) to fatty acyl-CoAs. Cardiac-specific ACSL1 knockout results in a shift towards glycolysis that promotes mTORC1-mediated ventricular hypertrophy. We used unbiased metabolomics and gene expression analyses to examine the early effects of genetic inactivation of FA oxidation on cardiac metabolism and function. 2. Methods and Results- Compared to WT hearts, global cardiac transcriptional analysis revealed differential expression of 245 genes in Acsl1H-/- hearts 2 weeks after Acsl1 ablation. Comparison of the 2- and 10-week transcriptional responses uncovered 139 genes whose expression was uniquely changed upon short-term cardiac inactivation of ACSL1. In particular, partial ACSL1 ablation led to the distinct upregulation of fibrosis genes, a phenomenon not observed after complete ACSL1 knockout. Metabolomic analysis identified 65 metabolites altered in hearts displaying partially reduced ACSL activity, whereas rapamycin treatment normalized the cardiac metabolomic fingerprint. Chronic mTOR inhibition via rapamycin treatment revealed novel mTORC1 targets involved in fibrosis, amino acid catabolism, and mitochondrial transport and metabolism. 3. Conclusions- Short-term cardiac-specific ACSL1 inactivation (Acsl1H-/-) resulted in metabolic and transcriptional derangements distinct from those observed upon complete ACSL1 knockout, leading to the identification of novel mTORC1 targets that regulate cardiac hypertrophy development, and suggesting heart-specific mTOR signaling that occurs during the early stages of substrate switching. Moreover, the rate of increased glucose use correlated negatively with hypertrophy development, strongly suggesting that hearts do not become hypertrophied if they can compensate or switch faster from FA to glucose use.
2018-04-27 | GSE103863 | GEO
Project description:Pathological cardiac hypertrophy is a major risk factor for the development of heart failure and sudden cardiac death, yet the molecular mechanism of cardiac hypertrophy is not fully understood. Recently, we found that the expression of Lin28a, a RNA-binding protein, was significantly upregulated during the early stages of cardiac hypertrophy. Interestingly, cardiac specific conditional deletion of Lin28a blunted pressure overload-induced cardiac hypertrophic responses. Given that Lin28a can bind to diverse mRNA to regulate their abundance and/or translation, we conducted RNA-seq to profile the cardiac transcriptome alteration without Lin28a under pressure overload. It showed that metabolic pathways, including glycolysis and biosynthetic pathway, were remarkedly affected. Thus, our study identifies Lin28a as a crucial regulator of cardiac hypertrophy via its role in metabolic programming.
2019-04-30 | GSE106897 | GEO
Project description:3 ventricles from E18.5 male mice were pooled for each array. Three arrays per genotype. Title: ERRγ Directs and Maintains the Transition to Oxidative Metabolism in the Post-Natal Heart; Abstract: At birth the heart undergoes a critical metabolic switch to transition from a predominant dependence on carbohydrates during fetal life to a greater dependence on postnatal oxidative metabolism. This remains the principle metabolic state throughout life; although pathologic conditions such as heart failure and cardiac hypertrophy reactivate components of the fetal genetic program to increase carbohydrate utilization. Disruption of the ERRγ gene, which is expressed at high levels in the fetal and postnatal mouse heart, blocks this switch resulting in lactatemia, electrocardiographic (ECG) abnormalities and death during the first week of life. Genomic ChIP-on-chip and expression analysis at E18.5 clearly identifies ERRγ as both a direct and indirect regulator of a nuclear-encoded mitochondrial genetic network that coordinates the postnatal metabolic transition. These findings reveal an unexpected and essential molecular genetic component of the oxidative metabolic gene program in the heart and highlight ERRγ in the study of cardiac hypertrophy and failure. Experiment Overall Design: Fetal mice were collected by caesarean secation. Hearts were stored in RNALater (Qiagen)
2009-04-30 | E-GEOD-8199 | biostudies-arrayexpress
Project description:Numerous studies found intestinal microbiota alterations which are thought to affect the development of various diseases through the production of gut-derived metabolites. However, the specific metabolites and their pathophysiological contribution to cardiac hypertrophy or heart failure progression still remain unclear. N,N,N-trimethyl-5-aminovaleric acid (TMAVA), derived from trimethyllysine through the gut microbiota, was elevated with gradually increased risk of cardiac mortality and transplantation in a prospective heart failure cohort (n=1647). TMAVA treatment aggravated cardiac hypertrophy and dysfunction in high-fat diet-fed mice. Decreased fatty acid oxidation (FAO) is a hallmark of metabolic reprogramming in the diseased heart and contributes to impaired myocardial energetics and contractile dysfunction. Proteomics uncovered that TMAVA disturbed cardiac energy metabolism, leading to inhibition of FAO and myocardial lipid accumulation. TMAVA treatment altered mitochondrial ultrastructure, respiration and FAO and inhibited carnitine metabolism. Mice with γ-butyrobetaine hydroxylase (BBOX) deficiency displayed a similar cardiac hypertrophy phenotype, indicating that TMAVA functions through BBOX. Finally, exogenous carnitine supplementation reversed TMAVA induced cardiac hypertrophy. These data suggest that the gut microbiota-derived TMAVA is a key determinant for the development of cardiac hypertrophy through inhibition of carnitine synthesis and subsequent FAO.
2021-12-08 | MTBLS3174 | MetaboLights
Project description:Numerous studies found intestinal microbiota alterations which are thought to affect the development of various diseases through the production of gut-derived metabolites. However, the specific metabolites and their pathophysiological contribution to cardiac hypertrophy or heart failure progression still remain unclear. N,N,N-trimethyl-5-aminovaleric acid (TMAVA), derived from trimethyllysine through the gut microbiota, was elevated with gradually increased risk of cardiac mortality and transplantation in a prospective heart failure cohort (n=1647). TMAVA treatment aggravated cardiac hypertrophy and dysfunction in high-fat diet-fed mice. Decreased fatty acid oxidation (FAO) is a hallmark of metabolic reprogramming in the diseased heart and contributes to impaired myocardial energetics and contractile dysfunction. Proteomics uncovered that TMAVA disturbed cardiac energy metabolism, leading to inhibition of FAO and myocardial lipid accumulation. TMAVA treatment altered mitochondrial ultrastructure, respiration and FAO and inhibited carnitine metabolism. Mice with γ-butyrobetaine hydroxylase (BBOX) deficiency displayed a similar cardiac hypertrophy phenotype, indicating that TMAVA functions through BBOX. Finally, exogenous carnitine supplementation reversed TMAVA induced cardiac hypertrophy. These data suggest that the gut microbiota-derived TMAVA is a key determinant for the development of cardiac hypertrophy through inhibition of carnitine synthesis and subsequent FAO.
2021-09-08 | PXD028230 |
Project description:Cardiac hypertrophy is an important and independent risk factor for the development of cardiac myopathy that may lead to heart failure. Cardiac hypertrophy manifests as an enlargement of the individual cardiomyocytes, which impairs the function of the heart. The only way to cure end-stage cardiac myopathy is by heart transplantation, a possibility limited due to lack of donor hearts. Therefore, early diagnosis of cardiac hypertrophy is needed in order to be able to initiate interventions that may prevent further progression of the disease. The mechanisms underlying the development of cardiac hypertrophy are yet not well understood. To increase the knowledge about mechanisms and regulatory pathways involved in the progression of cardiac hypertrophy, we have developed a human induced pluripotent stem cell (hiPSC)-based in vitro model of cardiac hypertrophy and performed extensive characterization of the model using multi-omics analyses. In a series of experiments, hiPSC-derived cardiomyocytes were stimulated with Endothelin-1 for 8, 24, 48 and 72 hours and their transcriptome and secreted proteome were analyzed thoroughly. The transcriptomic data show many enriched canonical pathways related to cardiac hypertrophy already at the earliest time point, e.g., cardiac hypertrophy signaling, actin cytoskeleton signaling and PI3K/AKT signaling. Cluster analysis of the differentially expressed genes showed that there are numerous clusters of genes that are dysregulated over the time period of 8 to 72h. An integrated transcriptome-secretome analysis enabled the identification of multimodal biomarkers of high relevance for monitoring early cardiac hypertrophy progression. Taken together, the results from this study demonstrate that our in vitro model displays a hypertrophic response on transcriptomic- and secreted proteomic level. The results also provide novel insight into the underlying mechanisms of cardiac hypertrophy and novel putative early cardiac hypertrophy biomarkers have been identified that will be further validated to assess their clinical relevance.
2022-02-16 | E-MTAB-11030 | 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