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- W2980477519 abstract "The absence of effective therapeutic treatments that can restore function in patients with heart failure necessitates the identification of new mechanisms and strategies to improve outcomes. Strategies that directly target the cardiomyocyte and have potential to increase metabolic capacity hold promise as treatment modalities. We sought to evaluate direct activators of the AMP-Activated Protein Kinase (AMPK) in a model of HF to test for improvements. The pan-AMPK activator PF-739 resulted in activation of AMPK, phosphorylation of the downstream target ACC, and increases in glucose uptake after a single dose in vivo. PF-739 resulted in an increase in the gene expression of relevant transcriptional regulators PGC1α and NR4a1, suggesting potential for beneficial effects on substrate metabolism in a HF model. PF-739 and the ACE inhibitor Enalipril were used in a combined TAC/MI model of mouse HF. 4 weeks after injury the animals treated with PF-739 had an increase in end systolic and diastolic volume and ejection fraction compared to vehicle animals. Enalipril treatment resulted in modest improvements in echo heart assessments and a reduction in heart weight compared to vehicle animals. To understand the mechanism for impaired heart function in HF we assessed the impact of PF-739 on systemic blood pressure, reasoning this could impact HF progression in the model. PF-739 caused an increase in blood pressure after acute dosing in mice and rats. A small molecule analogue of PF-739 differing in one methyl group with dramatically reduced AMPK activity was shown to have no detectable blood pressure effect, suggesting the blood pressure effects are related to AMPK activity. Contrary to expectation, treatment with PF-739 caused impairment in heart function in a mouse model of HF, an effect that may be the result of a systemic blood pressure effect of the compound." @default.
- W2980477519 created "2019-10-25" @default.
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- W2980477519 date "2019-08-02" @default.
- W2980477519 modified "2023-10-16" @default.
- W2980477519 title "Abstract 923: Pharmacological Activation of Ampk With a Direct Pan-ampk Activator Results in a Worsening of a Hf Phenotype in Mice" @default.
- W2980477519 doi "https://doi.org/10.1161/res.125.suppl_1.923" @default.
- W2980477519 hasPublicationYear "2019" @default.
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