Activation of the ERRα Transcriptional Pathway Alleviates Anthracycline-induced Cardiotoxicity by Improving Mitochondrial Metabolism
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ABSTRACT:
PROVIDER: PRJNA1233783 | ENA |
REPOSITORIES: ENA
Dataset's files
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| SRR32624538_1.fastq.gz | Fastqsanger.gz | |||
| SRR32624538_2.fastq.gz | Fastqsanger.gz | |||
| SRR32624539_1.fastq.gz | Fastqsanger.gz | |||
| SRR32624539_2.fastq.gz | Fastqsanger.gz | |||
| SRR32624540_1.fastq.gz | Fastqsanger.gz |
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Project description:Anthracycline-induced metabolic remodeling and mitochondrial damage are critical early events that contribute to cardiac dysfunction. However, the gene regulatory pathways governing the derangements in myocardial bioenergetics have not yet been fully delineated. Estrogen-related receptor alpha (ERRα) is a key regulator of energy metabolism, especially in tissues with high energy demands. Here, we demonstrate that ERRα acts as a beneficial modulator of mitochondrial metabolism in anthracycline-induced cardiotoxicity (AIC). ERRα gain-of-function enhances cardiomyocyte metabolism and mitochondrial function, thereby alleviating AIC. Conversely, cardiomyocyte-specific knockdown of ERRα exacerbates mitochondrial bioenergetic collapse and worsens heart failure phenotypes in AIC mice. Additionally, our research identifies a top-ranking isoflavone phytoestrogen as a novel ERRα agonist with favorable pharmacological properties. This compound promotes the transcriptional activity of metabolic genes, representing a significant step toward developing natural ERRα agonists for AIC therapy.
2025-03-07 | GSE291275 | GEO
Project description:Anthracycline-induced metabolic remodeling and mitochondrial damage are critical early events that contribute to cardiac dysfunction. However, the gene regulatory pathways governing the derangements in myocardial bioenergetics have not yet been fully delineated. Estrogen-related receptor alpha (ERRα) is a key regulator of energy metabolism, especially in tissues with high energy demands. Here, we demonstrate that ERRα acts as a beneficial modulator of mitochondrial metabolism in anthracycline-induced cardiotoxicity (AIC). ERRα gain-of-function enhances cardiomyocyte metabolism and mitochondrial function, thereby alleviating AIC. Conversely, cardiomyocyte-specific knockdown of ERRα exacerbates mitochondrial bioenergetic collapse and worsens heart failure phenotypes in AIC mice. Additionally, our research identifies a top-ranking isoflavone phytoestrogen as a novel ERRα agonist with favorable pharmacological properties. This compound promotes the transcriptional activity of metabolic genes, representing a significant step toward developing natural ERRα agonists for AIC therapy.
2025-03-12 | GSE291450 | GEO
Project description:Activation of the ERRα Transcriptional Pathway Alleviates Anthracycline-induced Cardiotoxicity by Improving Mitochondrial Metabolism
| PRJNA1232698 | ENA
Project description:Doxorubicin (DOX) and other anthracyclines are effective chemotherapeutic agents, however, their use is influenced by the risk of cardiotoxicity. We still have an incomplete understanding of the cardiomyocyte protective pathways activated after anthracycline-induced cardiotoxicity (AIC).Danshen injection (DSI), astaxanthin (AXT) and diosmetin (DMT) are effective in the treatment of cardiovascular diseases, but the mechanism of protection against adriamycin-induced cardiotoxicity is unclear. Here, we performed RNA-seq screening in H9c2 cardiomyocytes to determine the potential protective mechanisms of Danshen injection, astaxanthin and diosmetin against AIC.
2024-10-30 | GSE246548 | GEO
Project description:The effort to utilize microflow liquid chromatography for deep-scale proteomic analysis (µLC-MS/MS) is still growing. In this work, we utilized two-dimensional LC separation and peptide derivatization by tandem mass tag and assessed the capability of µLC-MS/MS to reveal protein changes associated with severe anthracycline-induced cardiomyopathy phenotype in comparison with nLC-MS/MS. Finally, control and rabbit myocardium specimens with experimentally induced anthracycline cardiomyopathy were analysed. Nearly 4000 myocardial proteins were quantified using µLC-MS/MS. In concordance with nLC-MS/MS, data evaluation revealed that severe anthracycline cardiotoxicity phenotype was associated with marked global protein dysregulation. Observed protein dysregulation consisted of profound remodelling of cardiomyocyte sarcomere as well as components of extracellular matrix. Pro-inflammatory proteins and multiple antioxidant proteins were markedly changed, whereas the levels of mitochondrial proteins were declined compared to control myocardium. In this study, µLC-MS/MS was confirmed as a versatile proteomic tool for comprehensive mapping of proteome changes related to anthracycline cardiotoxicity having a great potential to become full-fledged alternative to nLC.
2025-04-30 | PXD047014 | Pride
Project description:The administration of anthracycline drugs induces progressive and dose-related cardiac damage through several cytotoxic mechanisms, including endoplasmic reticulum (ER) stress. The unfolded protein response plays a crucial role for mitigating misfolded protein accumulation induced by excessive ER stress. We aimed to clarify whether endoplasmic reticulum-selective autophagy machinery (ER-phagy) serves as an alternative system to protect cardiomyocytes from ER stress caused by anthracycline drugs. Primary cultured cardiomyocytes, H9c2 cell lines, and cardiomyocyte-specific transgenic mice, all expressing ss-RFP-GFP-KDEL proteins, were used as ER-phagy reporter models. We generated loss-of-function models using RNA interference or gene-trap mutagenesis techniques. We assessed phenotypes and molecular signaling pathways using immunoblotting, quantitative polymerase chain reaction, cell viability assays, immunocytochemical and histopathological analyses, and cardiac ultrasonography. The administration of doxorubicin (Dox) activated ER-phagy in ss-RFP-GFP-KDEL-transduced cardiomyocytes. In addition, Dox-induced cardiomyopathy models of ER-phagy reporter mice showed marked activation of ER-phagy in the myocardium compared to those of saline-treated mice. Quantitative polymerase chain reaction analyses revealed that Dox enhanced the expression of cell-cycle progression gene 1 (CCPG1), one of the ER-phagy receptors, in H9c2 cells. Ablation of CCPG1 in H9c2 cells resulted in the reduced ER-phagy activity, accumulation of proapoptotic proteins, and deterioration of cell survival against Dox administration. CCPG1-hypomorphic mice developed more severe deterioration in systolic function in response to Dox compared to wild-type mice. Our findings highlight a compensatory role of CCPG1-driven ER-phagy in reducing Dox toxicity. With further study, ER-phagy may be a potential therapeutic target to mitigate Dox-induced cardiomyopathy.
| S-EPMC10635891 | biostudies-literature
Project description:mTOR and ERRα are key regulators of common metabolic processes. However, the extent of functional overlap between these two factors has not been investigated. ChIP-sequencing analyses on mouse liver reveal mTOR recruitment to regulatory regions of genes on a genome-wide scale including enrichment at genes shared with ERRα that are involved in the TCA cycle and lipogenesis pathway. A total of 9469 and 23226 peaks were identified for mTOR and ERRα ChIP-seq datasets, respectively. mTOR and ERRα mouse liver ChIP-seq datasets obtained from pooling 8 individual ChIPs from a chromatin pool of 26 livers.
2013-04-03 | E-GEOD-43638 | biostudies-arrayexpress
Project description:Anthracyclines such as doxorubicin (Dox) are effective chemotherapeutic agents, however their use is hampered by subsequent cardiotoxicity risk. Our understanding of cardiomyocyte protective pathways activated following anthracycline-induced cardiotoxicity (AIC) remains incomplete. Insulin-like growth factor binding protein (IGFBP) 3 (Igfbp-3), the most abundant IGFBP family member in the circulation, is associated with effects on the metabolism, proliferation, and survival of various cells. Whereas Igfbp-3 is induced by Dox in the heart, its role in AIC is ill-defined. We investigated molecular mechanisms as well as systems-level transcriptomic consequences of manipulating Igfbp-3 in AIC using neonatal rat ventricular myocytes and human induced pluripotent stem cell-derived cardiomyocytes.
2022-06-28 | GSE206803 | GEO
Project description:Objective Estrogen-related-receptor α (ERRα) plays a critical role in the transcriptional regulation of cellular bioenergetics and metabolism, and perturbations in its activity have been associated with metabolic diseases. While several coactivators and corepressors of ERRα have been identified to date, a knowledge gap remains in understanding the extent to which ERRα cooperates with coregulators in the control of gene expression. Herein, we mapped the primary chromatin-bound ERRα interactome in mouse liver. Methods RIME (Rapid Immuno-precipitation Mass spectrometry of Endogenous proteins) analysis using mouse liver samples from two circadian time points was used to catalog ERRα-interacting proteins on chromatin. The genomic crosstalk between ERRα and its identified cofactors in the transcriptional control of precise gene programs was explored through cross-examination of genome-wide binding profiles from chromatin immunoprecipitation-sequencing (ChIP-seq) studies. The dynamic interplay between ERRα and its newly uncovered cofactor Host cell factor C1 (HCFC1) was further investigated by loss-of-function studies in hepatocytes. Results Characterization of the hepatic ERRα chromatin interactome led to the identification of 48 transcriptional interactors of which 42 were previously unknown including HCFC1. Interrogation of available ChIP-seq binding profiles highlighted oxidative phosphorylation (OXPHOS) under the control of a complex regulatory network between ERRα and multiple cofactors. While ERRα and HCFC1 were found to bind to a large set of common genes, only a small fraction showed their co-localization, found predominately near the transcriptional start sites of genes particularly enriched for components of the mitochondrial respiratory chain. Knockdown studies demonstrated inverse regulatory actions of ERRα and HCFC1 on OXPHOS gene expression ultimately dictating the impact of their loss-of-function on mitochondrial respiration. Conclusions Our work unveils a repertoire of previously unknown transcriptional partners of ERRα comprised of chromatin modifiers and transcription factors thus advancing our knowledge of how ERRα regulates metabolic transcriptional programs.
2024-06-22 | PXD047767 | Pride
Project description:Functional oncogenic links between ErbB2 and ERRα in HER2+ breast cancer patients support a therapeutic benefit of co-targeted therapies. However, ErbB2 and ERRα also play key roles in heart physiology, and this approach could pose a potential liability to cardiovascular health. Herein, using integrated phosphoproteomic, transcriptomic and metabolic profiling, we uncovered molecular mechanisms associated with the adverse remodeling of cardiac functions in mice with combined attenuation of ErbB2 and ERRα activity. Genetic disruption of both effectors results in profound effects on cardiomyocyte architecture, inflammatory response and metabolism, the latter leading to a decrease in fatty acyl-carnitine species further increasing the reliance on glucose as a metabolic fuel, a hallmark of failing hearts. Furthermore, integrated omics signatures of ERRα loss-of-function and doxorubicin treatment exhibit common features of chemotherapeutic cardiotoxicity. These findings thus reveal potential cardiovascular risks in discrete combination therapies in the treatment of breast and other cancers.
2022-09-20 | MTBLS795 | MetaboLights