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NRF2 activator-treated human cardiac spheres have enhanced maturation and enable disease modeling

ABSTRACT: NRF2 activator-treated human cardiac spheres have enhanced maturation and enable disease modeling

PROVIDER: PRJNA846342 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR19552231_1.fastq.gz	Fastqsanger.gz
	SRR19552231_2.fastq.gz	Fastqsanger.gz
	SRR19552232_1.fastq.gz	Fastqsanger.gz
	SRR19552232_2.fastq.gz	Fastqsanger.gz
	SRR19552233_1.fastq.gz	Fastqsanger.gz

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NRF2 activator-treated human cardiac spheres have enhanced maturation and enable disease modeling

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AMPK activator-treated human cardiac spheres have enhanced maturation and enable pathological modeling

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AMPK activator-treated human cardiac spheres enhance maturation and enable pathological modeling.

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:Oltipraz is an activator of Nrf2 but is also an activator of other pathways including those mediated by constitutive activated receptor (CAR). To identify genes regulated by oltipraz that were Nrf2-dependent, we compared gene expression after exposure in wild-type and Nrf2-null mice. Wild-type or Nrf2-null mice were treated each day for 4 days with 75 mg/kg/day/day oltipraz in corn oil or corn oil alone. There were 4 biological replicates used for each of the 4 genotype-treatment groups. Gene expression in the livers of the mice was evaluated using Affymetrix mouse exon arrays (MoEx-1_0-st-v1).

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