Ferroptosis is essential for diabetic cardiomyopathy and is prevented by sulforaphane via AMPK/NRF2 pathways

查看全文 作　　者：Xiang [1,2]Wang;Xinxin [3]Chen;Wenqian [1,4]Zhou;Hongbo [1,2]Men;Terigen [1,2]Bao;Yike [1,2]Sun;Quanwei [2]Wang;Yi [1,4]Tan;Bradley [4,5,6]B.Keller;Qian [2]Tong;Yang [2]Zheng;Lu [1,4]Cai

机构地区：[1]Pediatric Research Institute,Department of Pediatrics,University of Louisville School of Medicine,Louisville,KY 40202,USA;[2]Department of Cardiovascular Disease,the First Hospital of Jilin University,Changchun 130021,China;[3]Department of Burn Surgery,First Hospital of Jilin University,Jilin University,Changchun 130021,China;[4]Department of Pharmacology and Toxicology,University of Louisville School of Medicine,Louisville,KY 40202,USA;[5]Pediatric Heart Research Program,Cardiovascular Innovation Institute,University of Louisville School of Medicine,Louisville,KY 40202,USA;[6]Cincinnati Children’s Heart Institute,Greater Louisville and Western Kentucky Practice,Louisville,KY 40202,USA

出　　处：《Acta Pharmaceutica Sinica B》索引2022年第12卷第2期,共15页

基　　金：supported in part by American Diabetes Association(1-18-IBS-082 to LC,USA);the National Key R&D Program of China(2016YFC0900903 to YZ,China)。 摘　　要：Herein,we define the role of ferroptosis in the pathogenesis of diabetic cardiomyopathy(DCM)by examining the expression of key regulators of ferroptosis in mice with DCM and a new ex vivo DCM model.Advanced glycation end-products(AGEs),an important pathogenic factor of DCM,were found to induce ferroptosis in engineered cardiac tissues(ECTs),as reflected through increased levels of Ptgs2 and lipid peroxides and decreased ferritin and SLC7 A11 levels.Typical morphological changes of ferroptosis in cardiomyocytes were observed using transmission electron microscopy.Inhibition of ferroptosis with ferrostatin-1 and deferoxamine prevented AGE-induced ECT remodeling and dysfunction.Ferroptosis was also evidenced in the heart of type 2 diabetic mice with DCM.Inhibition of ferroptosis by liproxstatin-1 prevented the development of diastolic dysfunction at 3 months after the onset of diabetes.Nuclear factor erythroid 2-related factor 2(NRF2)activated by sulforaphane inhibited cardiac cell ferroptosis in both AGE-treated ECTs and hearts of DCM mice by upregulating ferritin and SLC7 A11 levels.The protective effect of sulforaphane on ferroptosis was AMP-activated protein kinase(AMPK)-dependent.These findings suggest that ferroptosis plays an essential role in the pathogenesis of DCM;sulforaphane prevents ferroptosis and associated pathogenesis via AMPK-mediated NRF2 activation.This suggests a feasible therapeutic approach with sulforaphane to clinically prevent ferroptosis and DCM. 关键词：Advanced glycation end-products AMPK Cell death Diabetic cardiomyopathy Engineered cardiac tissue Ferroptosis Lipid peroxidation NRF2

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Ferroptosis is essential for diabetic cardiomyopathy and is prevented by sulforaphane via AMPK/NRF2 pathways

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