Dataset Information

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

ABSTRACT:

Background

Cardiac 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.

Methods

hiPSC-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.

Results

Treatment 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.

Conclusion

AMPK activator-treated cardiac spheres could serve as a valuable model to gain novel insights into cardiac diseases.

SUBMITTER: Li D

PROVIDER: S-EPMC10633979 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Publications

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

Li Dong D Armand Lawrence C LC Sun Fangxu F Hwang Hyun H Wolfson David D Rampoldi Antonio A Liu Rui R Forghani Parvin P Hu Xin X Yu Wen-Mei WM Qu Cheng-Kui CK Jones Dean P DP Wu Ronghu R Cho Hee Cheol HC Maxwell Joshua T JT Xu Chunhui C

Stem cell research & therapy 20231108 1

<h4>Background</h4>Cardiac 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.<h4>Methods</h4>hiPSC-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.<h4>Results</h4>Treatment of hiPSC-CMs with AMPK activators increased ATP content, mito ...[more]

PMID: 37941041

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Project description:Background: Liquiritin (LQ) is one of the main flavonoids extracted from the roots of Glycyrrhiza spp., which are widely used in traditional Chinese medicine. Studies in both cellular and animal disease models have shown that LQ attenuates or prevents oxidative stress, inflammation, and apoptosis. However, the potential therapeutic effects of LQ on pressure overload-induced cardiac hypertrophy have not been so far explored. Therefore, we investigated the cardioprotective role of LQ and its underlying mechanisms in the aortic banding (AB)-induced cardiac hypertrophy mouse model. Methods and Results: Starting 3 days after AB surgery, LQ (80 mg/kg/day) was administered daily over 4 weeks. Echocardiography and pressure-volume loop analysis indicated that LQ treatment markedly improved hypertrophy-related cardiac dysfunction. Moreover, hematoxylin and eosin, picrosirius red, and TUNEL staining showed that LQ significantly inhibited cardiomyocyte hypertrophy, interstitial fibrosis, and apoptosis. Western blot assays further showed that LQ activated LKB1/AMPKα2/ACC signaling and inhibited mTORC1 phosphorylation in cardiomyocytes. Notably, LQ treatment failed to prevent cardiac dysfunction, hypertrophy, and fibrosis in AMPKα2 knockout (AMPKα2-/-) mice. However, LQ still induced LKB1 phosphorylation in AMPKα2-/- mouse hearts. In vitro experiments further demonstrated that LQ inhibited Ang II-induced hypertrophy in neonatal rat cardiomyocytes (NRCMs) by increasing cAMP levels and PKA activity. Supporting the central involvement of the cAMP/PKA/LKB1/AMPKα2 signaling pathway in the cardioprotective effects of LQ, inhibition of Ang II-induced hypertrophy and induction of LKB1 and AMPKα phosphorylation were no longer observed after inhibiting PKA activity. Conclusion: This study revealed that LQ alleviates pressure overload-induced cardiac hypertrophy in vivo and inhibits Ang II-induced cardiomyocyte hypertrophy in vitro via activating cAMP/PKA/LKB1/AMPKα2 signaling. These findings suggest that LQ might be a valuable adjunct to therapeutic approaches for treating pathological cardiac remodeling.

Dataset Information

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

Background

Methods

Results

Conclusion

Publications

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

Similar Datasets

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