NRF2 activator-treated human cardiac spheres have enhanced maturation and enable disease modeling
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE205566 | GEO | 2022/06/08
REPOSITORIES: GEO
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Project description:The activation of the transcription factor NF-E2-related factor 2 (Nrf2) maintains cellular homeostasis in response to oxidative stress by the regulation of multiple cytoprotective genes. Without stressors the activity of Nrf2 is inhibited by its interaction with the kelch-like ECH-associated protein 1 (Keap1). Here, we describe RA839, a small molecule that binds non-covalently to the Nrf2-interacting kelch domain of Keap1 with a Kd of approximately 6 µM, as demonstrated by X-ray co-crystallization and isothermal titration calorimetry. Whole-genome DNA arrays showed that at 10 µM RA839 significantly regulated 105 genes in bone marrow-derived macrophages. Canonical pathway mapping of these genes revealed an activation of pathways linked with Nrf2 signalling. These pathways were also activated after the activation of Nrf2 by the silencing of Keap1 expression. RA839 regulated only two genes in Nrf2 knockout macrophages. Similar to the activation of Nrf2 by either silencing of Keap1 expression or by the reactive compound CDDO-Me, RA839 prevented the induction of both inducible nitric oxide synthase expression and nitric oxide release in response to lipopolysaccharides in macrophages. In mice RA839 acutely induced Nrf2-target gene expression in liver. RA839 is a selective inhibitor of the Keap1/Nrf2 interaction and a useful tool compound to study the biology of Nrf2. Gene expression profile of bone marrow derived murine macrophages (BMDM) from Nrf2+/+ or Nrf2-/- mice treated with RA838, siKeap1-1 or siKeap1-2 were compared to untreated DMSO control or siControl. Four biological replicates were used for each sample group.
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Project description:NRF2 activator-treated human cardiac spheres have enhanced maturation and enable disease modeling
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Project description:Genetic versus chemoprotective activation of Nrf2 signaling: overlapping yet distinct hepatic gene expression profiles between Keap1 knockout and triterpenoid treated mice; Loss of Nrf2 signaling increases susceptibility to acute toxicity, inflammation, and carcinogenesis in mice due to the inability to mount adaptive responses. By contrast, disruption of Keap1 (a cytoplasmic modifier of Nrf2 turnover) protects against these stresses in mice; although dominant negative mutations in Keap1 have been identified recently in some human cancers. Global characterization of Nrf2 activation is important to exploit this pathway for chemoprevention in healthy, yet at-risk individuals and also to elucidate the consequences of hijacking the pathway in Keap1-mutant human cancers. This analysis also enables a global characterization of the pharmacodynamic action of CDDO-Im at a low dose that is relevant to chemoprevention. Experiment Overall Design: Liver-targeted conditional Keap1-null (CKO) mice provide a model of genetic activation of Nrf2 signaling. By coupling global gene expression analysis of CKO mice with analysis of pharmacologic activation using the synthetic oleanane triterpenoid CDDO-Im, we are able to gain insight into pathways affected by Nrf2 activation. CDDO-Im is an extremely potent activator of Nrf2 signaling. CKO mice were used to identify genes modulated by genetic activation of Nrf2 signaling. The CKO response was compared to hepatic global gene expression changes in wild-type mice treated with CDDO-Im at a maximal Nrf2 activating dose. n=3/group, male 9 week old mice were used. Mice were treated with a single dose of vehicle (10% Cremophor-EL, 10% DMSO, and PBS) or 30 umol CDDO-Im/kg body weight by gavage and sacrificed 6 h later.
2009-05-11 | E-GEOD-15633 | biostudies-arrayexpress
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Project description:BackgroundCardiac pathological outcome of metabolic remodeling is difficult to model using cardiomyocytes derived from human-induced pluripotent stem cells (hiPSC-CMs) due to low metabolic maturation.MethodshiPSC-CM spheres were treated with AMP-activated protein kinase (AMPK) activators and examined for hiPSC-CM maturation features, molecular changes and the response to pathological stimuli.ResultsTreatment of hiPSC-CMs with AMPK activators increased ATP content, mitochondrial membrane potential and content, mitochondrial DNA, mitochondrial function and fatty acid uptake, indicating increased metabolic maturation. Conversely, the knockdown of AMPK inhibited mitochondrial maturation of hiPSC-CMs. In addition, AMPK activator-treated hiPSC-CMs had improved structural development and functional features-including enhanced Ca2+ transient kinetics and increased contraction. Transcriptomic, proteomic and metabolomic profiling identified differential levels of expression of genes, proteins and metabolites associated with a molecular signature of mature cardiomyocytes in AMPK activator-treated hiPSC-CMs. In response to pathological stimuli, AMPK activator-treated hiPSC-CMs had increased glycolysis, and other pathological outcomes compared to untreated cells.ConclusionAMPK activator-treated cardiac spheres could serve as a valuable model to gain novel insights into cardiac diseases.
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Project description:Nrf2 null mice administered CDDO-IM
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Project description:The transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates an array of cytoprotective genes, yet studies in transgenic mice have led to conflicting reports on its role in liver regeneration. We aimed to test the hypothesis that pharmacological activation of Nrf2 would enhance liver regeneration. Wild type (WT) and Nrf2 null mice were administered bardoxolone methyl (CDDO-Me), a potent activator of Nrf2 that has entered clinical development, and then subjected to partial hepatectomy (PHx). CDDO-Me enhanced the rate of restoration of liver volume and improved liver function (multispectral optoacoustic imaging in wild type, but not Nrf2 null, mice following two-thirds partial hepatectomy. These effects were associated with an increase in hepatocyte hypertrophy and proliferation, the suppression of immune and inflammatory signals, and metabolic remodeling in the remnant liver tissue.
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Project description:Nrf2 (NF-E2-related-factor-2) contributes to the maintenance of glucose homeostasis in vivo. Nrf2 suppresses blood glucose levels by protecting pancreatic β-cells from oxidative stress and improving peripheral tissue glucose utilization. To elucidate the molecular mechanisms by which Nrf2 contributes to the maintenance of glucose homeostasis, we generated skeletal muscle (SkM)-specific Keap1-knockout (Keap1MuKO) mice that express abundant Nrf2 in SkM and then examined Nrf2-target gene expression in this tissue. In Keap1MuKO mice, blood glucose levels were significantly downregulated, and the levels of glycogen branching enzyme (Gbe1) mRNA, along with those of glycogen branching enzyme (GBE) protein, were significantly upregulated in mouse SkM. Consistent with this result, chemical Nrf2-inducers promoted Gbe1 mRNA expression in both mouse SkM and C2C12 myotubes. Chromatin-immunoprecipitation analysis demonstrated that Nrf2 binds the Gbe1 upstream promoter regions. In Keap1MuKO mice, muscle glycogen content was strongly reduced, and forced GBE expression in C2C12 myotubes promoted glucose uptake. Therefore, our results demonstrate that Nrf2-induction in SkM increases GBE expression and reduces muscle glycogen content, resulting in improved glucose tolerance. Chromatin occupancy of Nrf2 under CDDO-Im-treated condition were generated by deep sequencing, in dupliplicate
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