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Novel pan-ERR agonists ameliorate heart failure through enhancing cardiac fatty acid metabolism and mitochondrial function

ABSTRACT: Novel pan-ERR agonists ameliorate heart failure through enhancing cardiac fatty acid metabolism and mitochondrial function

PROVIDER: PRJNA1006357 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25665166_1.fastq.gz	Fastqsanger.gz
	SRR25665166_2.fastq.gz	Fastqsanger.gz
	SRR25665167_1.fastq.gz	Fastqsanger.gz
	SRR25665167_2.fastq.gz	Fastqsanger.gz
	SRR25665168_1.fastq.gz	Fastqsanger.gz

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Novel pan-ERR agonists ameliorate heart failure through enhancing cardiac fatty acid metabolism and mitochondrial function

Project description:Cardiac metabolic dysfunction is a hallmark of heart failure. Estrogen related receptors ERRalpha and ERRgamma are essential regulators of cardiac metabolism. Therefore, activation of ERR could be a potential theraputic intervention for heart failure. However, in vivo studies demonstrating the potential utility of ERR agonists for heart failure treatment are lacking, as compounds with pharmackinetics appropriate for in vivo use have not been available. Using a structure-based design approach, we designed and synthesized two structurally distinct pan-ERR agonists, SLU-PP-332 (332) and SLU-PP-915 (915), which significantly improved ejection fraction, ameliorated fibrosis and increased survival associated with pressure overload-induced heart failure without affecting cardiac hypertrophy. Mechanistically, a broad spectrum of metabolic genes was transcriptionally activated by ERR agonists, particulary genes involved in fatty acid metabolism and mitochondrial function. Using both in vitro and in vivo genetic dependency experiments, we show that ERRgamma is the main mediatorof ERR agonism-induced transcriptional regulation and cardioprotection and definitively demonstrated target specificity. Additionally, ERR agonism also led to downregulation of cell cycle and development pathways, which was partially mediated by E2F1 in cardiomyocyte. In summary, ERR agonists maintain oxidative metabolism, which confers cardiac protection against pressure overload-induced heart failure in vivo. Our results provide direct pharmacological evidence supporting the further in vivo development of ERR agonists as novel heart failure theraputics.

2024-01-01 | GSE241075 | GEO

Novel pan-ERR agonists ameliorate heart failure through enhancing cardiac fatty acid metabolism and mitochondrial function

2023-11-21 | GSE239912 | GEO

Novel pan-ERR agonists ameliorate heart failure through enhancing cardiac fatty acid metabolism and mitochondrial function

Project description:Novel pan-ERR agonists ameliorate heart failure through enhancing cardiac fatty acid metabolism and mitochondrial function

| PRJNA1001375 | ENA

Rhizobium sp. ERR 922 isolate:ERR 922

Project description:Rhizobium sp. ERR 922 isolate:ERR 922 Genome sequencing and assembly

| PRJNA536632 | ENA

Rhizobium sp. ERR 942 isolate:ERR 942

Project description:Rhizobium sp. ERR 942 isolate:ERR 942 Genome sequencing and assembly

| PRJNA536631 | ENA

Identification of Selective ERR? Inverse Agonists.

Project description:GSK5182 (4) is currently one of the lead compounds for the development of estrogen-related receptor gamma (ERR?) inverse agonists. Here, we report the design, synthesis, pharmacological and in vitro absorption, distribution, metabolism, excretion, toxicity (ADMET) properties of a series of compounds related to 4. Starting from 4, a series of analogs were structurally modified and their ERR? inverse agonist activity was measured. A key pharmacophore feature of this novel class of ligands is the introduction of a heterocyclic group for A-ring substitution in the core scaffold. Among the tested compounds, several of them are potent ERR? inverse agonists as determined by binding and functional assays. The most promising compound, 15g, had excellent binding selectivity over related subtypes (IC50 = 0.44, >10, >10, and 10 ?M at the ERR?, ERR?, ERR?, and ER? subtypes, respectively). Compound 15g also resulted in 95% transcriptional repression at a concentration of 10 ?M, while still maintaining an acceptable in vitro ADMET profile. This novel class of ERR? inverse agonists shows promise in the development of drugs targeting ERR?-related diseases.

| S-EPMC6273807 | biostudies-literature

Quantitative Analysis of ERR gamma-driven pancreatic acinar cell transcriptome

Project description:The goal of this study is to compare NGS-derived pancreatic acinar cell-based transcriptome profiling (RNA-seq) to evaluate ERR gamma-driven transcriptional program

2020-11-19 | GSE161757 | GEO

The orphan nuclear hormone receptor ERR-beta controls rod photoreceptor survival.

Project description:Mutation of rod photoreceptor-enriched transcription factors is a major cause of inherited blindness. We identified the orphan nuclear hormone receptor ERRÎ² as selectively expressed in rod photoreceptors. Overexpression of ERRÎ² induces expression of rod-specific genes in retinas of both wildtype and in Nrl-/- mice, which lack rod photoreceptors. Mutation of ERRÎ² results in dysfunction and degeneration of rods, while inverse agonists of ERRÎ² trigger rapid rod degeneration, which is rescued by constitutively active mutants of ERRÎ². ERRÎ² coordinates expression of multiple genes that are rate-limiting regulators of ATP generation and consumption in photoreceptors. Furthermore, enhancing ERRÎ² activity rescues photoreceptor defects that result from loss of the photoreceptor-specific transcription factor Crx. Our findings demonstrate that ERRÎ² is a critical regulator of rod photoreceptor function and survival, and suggest that ERRÎ² agonists may be useful in the treatment of certain retinal dystrophies. Affymetrix MOE430 microarrays were used to analyze the expression patterns of P21 mouse retinal tissues. The results were compared across the variable of Genotype, specifically ERRÎ² knockout versus wildtype.

2010-07-30 | E-GEOD-21944 | biostudies-arrayexpress

Rhizobium sp. ERR 1071 isolate:ER1071

Project description:Rhizobium sp. ERR 1071 genome sequencing

| PRJNA536633 | ENA

Integrated multi-omics analysis of adverse cardiac remodeling and metabolic inflexibility upon ErbB2 and ERR⍺ deficiency

Project description:Functional oncogenic links between ErbB2 and ERR⍺ in HER2+ breast cancer patients support a therapeutic benefit of co-targeted therapies. However, ErbB2 and ERR⍺ also play key roles in heart physiology, and this approach could pose a potential liability to cardiovascular health. 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 ERR⍺ 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 ERR⍺ loss-of-function and doxorubicin treatment exhibit reciprocal features of chemotherapeutic cardiotoxicity. These findings thus reveal potential cardiovascular risks in discrete combination therapies in the treatment of breast and other cancers.

2022-09-19 | GSE199150 | GEO

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