Activation of protein kinase B rescues against thapsigargin-elicited cardiac dysfunction through regulation of NADPH oxidase and ferroptosis.

Autor: Wang X; Department of Cardiology, Fuwai Central China Cardiovascular Hospital, Henan Provincial People's Hospital Heart Center, Zhengzhou, 451464, China., Li FJ; Department of Cardiovascular Medicine, The First Affiliated Hospital, Jinan University, Guangzhou, 510660, China., Cheng Y; Department of Cardiovascular Medicine, The Sixth People's Hospital of Zhengzhou, Zhengzhou, Henan, 450000, China., Chen S; Department of Cardiology, Xinfeng People's Hospital, Shaoguan, 511199, China., Zhu S; The Cardiovascular Medicine Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 451162, China., Zhang Y; Department of Cardiology, Zhongshan Hospital Fudan University, Shanghai, 200032, China; Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital Fudan University, Shanghai, 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai, 200032, China., Reiter RJ; Department of Cell Systems and Anatomy, UT Health San Antonio, TX, USA., Ashrafizadeh M; Department of General Surgery and Institute of Precision Diagnosis and Treatment of Digestive System Tumors, Carson International Cancer Center, Shenzhen University General Hospital, Shenzhen University, Shenzhen, Guangdong, 518055, China., Lin J; Department of Cardiology, Zhongshan Hospital Fudan University, Shanghai, 200032, China; Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital Fudan University, Shanghai, 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai, 200032, China., Wang G; Department of Emergency, Shanghai Tenth People's Hospital, School of Medicine Tongji University, Shanghai, 200072, China. Electronic address: guizhen-wang@163.com., Lin L; Department of Cardiology, Zhongshan Hospital Fudan University, Shanghai, 200032, China; Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital Fudan University, Shanghai, 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai, 200032, China. Electronic address: linglin@fudan.edu.cn., Ren J; Department of Cardiology, Zhongshan Hospital Fudan University, Shanghai, 200032, China; Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital Fudan University, Shanghai, 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai, 200032, China. Electronic address: ren.jun@zs-hospital.sh.cn.
Jazyk: angličtina
Zdroj: Chemico-biological interactions [Chem Biol Interact] 2025 Jan 05; Vol. 405, pp. 111292. Date of Electronic Publication: 2024 Oct 29.
DOI: 10.1016/j.cbi.2024.111292
Abstrakt: Endoplasmic reticulum (ER) stress is a known contributor to cardiac remodeling and contractile dysfunction. Although NADPH oxidase has been implicated in ER stress-induced organ damage, its specific role in myocardial complications resulting from ER stress remains unclear. This study aimed to investigate the possible involvement of NADPH oxidase in ER stress-induced myocardial abnormalities and to evaluate the impact of Akt constitutive activation on these myocardial defects. Mice with cardiac-specific overexpression of active mutant of Akt (Myr-Akt) and their wild-type (WT) littermates were treated with ER stress instigator thapsigargin (1 mg/kg, i. p. 72 hrs) before evaluating myocardial morphology and function. Our results noted that thapsigargin significantly impaired echocardiographic parameters and cell shortening indices, including elevated LVESD, decreased ejection fraction, fractional shortening, peak shortening, electrically-stimulated intracellular Ca 2+ release, and cardiomyocyte survival. These functional deteriorations were accompanied by upregulation of NADPH oxidase, O 2 - production, mitochondrial damage, carbonyl formation, lipid peroxidation, apoptosis, and interstitial fibrosis, with unchanged myocardial size. Constitutive Akt hyperactivation did not generate any response on myocardial morphology and function, although it greatly suppressed or nullified thapsigargin-induced myocardial remodeling and dysfunction. Thapsigargin also triggered dephosphorylation of Akt and its downstream signal GSK3β, along with development of ferroptosis, all of which were nullified by Akt hyperactivation. In vitro studies further revealed that thapsigargin provoked cardiomyocyte mechanical anomalies and lipid peroxidation, similar to in vivo results. These effects were reverted by inhibitors of NADPH oxidase and ferroptosis (apocynin and LIP1). Collectively, our data denote an important protective role for Akt hyperactivation in thapsigargin-evoked myocardial anomalies, likely through NADPH oxidase-mediated regulation of ferroptosis.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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