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Dexmedetomidine attenuates myocardial ischemia/reperfusion-induced ferroptosis via AMPK/GSK-3β/Nrf2 axis

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机构: [1]Department of Anesthesiology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
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The present study aimed to investigate whether dexmedetomidine (Dex) exerts cardioprotection effect through inhibiting ferroptosis. Myocardial ischemia/reperfusion injury (MIRI) was induced in Sprague-Dawley rats in Langendorff preparation. The hemodynamic parameters were recorded. Triphenyltetrazolium chloride (TTC) staining was used to determine infarct size. In the in vitro study, the model of hypoxia/reoxygenation (HR) was established in H9c2 cells. Cell viability and apoptosis were detected using cell counting kit 8 (CCK-8), and AV/PI dual staining respectively. Lipid peroxidation as measured by the fluorescence of the fatty acid analog C11-BODIPY581/591 probe and intracellular ferrous iron levels were measured by fluorescence of Phen Green SK (PGSK) probe, whereas immunofluorescence and transmission electron microscopy were also used to examine ferroptosis. Protein levels were investigated by Western blot. The interactions of AMPK/GSK-3β signaling with Nrf2 were also assessed through AMPK inhibition and GSK-3β overexpression. Our findings indicated that Dex significantly alleviated myocardial infarction, improved heart function, and decreased HR-induced accumulation of Fe2+ and lipid peroxidation in cardiomyocytes. Dex significantly increased the expression levels of Nrf2, SLC7A11, and GPX4. However, inhibition of Nrf2 by ML385 blunted the protective effect of Dex in HR-treated H9c2 cells. Inhibition of AMPK with a specific inhibitor or siRNA decreased the expression levels of phosphorylation of GSK-3β and Nrf2 induced by Dex. Overexpression of GSK-3β resulted in lower levels of nuclear Nrf2, whereas depression of GSK-3β enhanced expressions of nuclear Nrf2. In conclusion, Dex protects hearts against MIRI-induced ferroptosis via activation of Nrf2 through AMPK/GSK-3β signaling pathway.Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

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出版当年[2023]版:
大类 | 2 区 医学
小类 | 1 区 药学 2 区 医学:研究与实验
最新[2023]版:
大类 | 2 区 医学
小类 | 1 区 药学 2 区 医学:研究与实验
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出版当年[2022]版:
Q1 MEDICINE, RESEARCH & EXPERIMENTAL Q1 PHARMACOLOGY & PHARMACY
最新[2023]版:
Q1 MEDICINE, RESEARCH & EXPERIMENTAL Q1 PHARMACOLOGY & PHARMACY

影响因子: 最新[2023版] 最新五年平均 出版当年[2022版] 出版当年五年平均 出版前一年[2021版] 出版后一年[2023版]

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第一作者机构: [1]Department of Anesthesiology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
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通讯机构: [1]Department of Anesthesiology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China [*1]Department of Anesthesiology, First Affiliated Hospital of Kunming Medical University, 295 Xichang Road, Kunming, Yunnan 650032, PR China.
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