Metallothionein Alleviates Glutathione Depletion-Induced Oxidative Cardiomyopathy through CISD1-Dependent Regulation of Ferroptosis in Murine Hearts.

Autor:	Li FJ; Department of Cardiovascular Medicine, The First Affiliated Hospital, Jinan University, Guangzhou, China., Fu S; Department of ICU/Emergency, Wuhan Third Hospital, Wuhan University, Wuhan, China., Ye H; Department of Burns, Nanfang Hospital, Southern Medical University, Guangzhou, China; Department of Burns and Plastic and Wound Repair, Ganzhou People's Hospital, Ganzhou, China., Hu YH; Department of Cardiovascular Medicine, The First Affiliated Hospital, Jinan University, Guangzhou, China., Chen J; Department of Cardiovascular Medicine, The First Affiliated Hospital, Jinan University, Guangzhou, China., Privratsky JR; Center for Perioperative Organ Protection, Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina., Yu W; School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, Xianning, China., Dong F; Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio., Reiter RJ; Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, Texas., Dong M; Department of Burns, Nanfang Hospital, Southern Medical University, Guangzhou, China., Guo J; Department of Cardiovascular Medicine, The First Affiliated Hospital, Jinan University, Guangzhou, China. Electronic address: guojun2009@jnu.edu.cn., Ren J; National Clinical Research Center for Interventional Medicine, Shanghai, China; Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China. Electronic address: ren.jun@zs-hospital.sh.cn.
Jazyk:	angličtina
Zdroj:	The American journal of pathology [Am J Pathol] 2024 Jun; Vol. 194 (6), pp. 912-926. Date of Electronic Publication: 2024 Feb 28.
DOI:	10.1016/j.ajpath.2024.02.009
Abstrakt:	This study was designed to discern the effect of heavy scavenger metallothionein on glutathione (GSH) deprivation-evoked cardiac anomalies and mechanisms involved with an emphasis on ferroptosis. Wild-type and cardiac metallothionein transgenic mice received GSH synthase inhibitor buthionine sulfoximine (BSO; 30 mmol/L in drinking water) for 14 days before assessment of myocardial morphology and function. BSO evoked cardiac remodeling and contractile anomalies, including cardiac hypertrophy, interstitial fibrosis, enlarged left ventricular chambers, deranged ejection fraction, fraction shortening, cardiomyocyte contractile capacity, intracellular Ca 2+ handling, sarcoplasmic reticulum Ca 2+ reuptake, loss of mitochondrial integrity (mitochondrial swelling, loss of aconitase activity), mitochondrial energy deficit, carbonyl damage, lipid peroxidation, ferroptosis, and apoptosis. Metallothionein itself did not affect myocardial morphology and function, although it mitigated BSO-provoked myocardial anomalies, loss of mitochondrial integrity and energy, and ferroptosis. Immunoblotting revealed down-regulated sarco(endo)plasmic reticulum Ca 2+ -ATPase 2a, glutathione peroxidase 4, ferroptosis-suppressing CDGSH iron-sulfur domain 1 (CISD1), and mitochondrial regulating glycogen synthase kinase-3β phosphorylation with elevated p53, myosin heavy chain-β isozyme, IκB phosphorylation, and solute carrier family 7 member 11 (SLC7A11) as well as unchanged SLC39A1, SLC1A5, and ferroptosis-suppressing protein 1 following BSO challenge, all of which, except glutamine transporter SLC7A11 and p53, were abrogated by metallothionein. Inhibition of CISD1 using pioglitazone nullified GSH-offered benefit against BSO-induced cardiomyocyte ferroptosis and contractile and intracellular Ca 2+ derangement. Taken together, these findings support a regulatory modality for CISD1 in the impedance of ferroptosis in metallothionein-offered protection against GSH depletion-evoked cardiac aberration. Competing Interests: Disclosure Statement None declared. (Copyright © 2024 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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