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 SLC7A11 levels.Typical morphological changes of ferroptosis in cardiomyocytes were observed using transmission electron mi-croscopy.Inhibition of ferroptosis with ferrostatin-1 and deferoxamine prevented AGE-induced ECT re-modeling 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 SLC7A11 levels.The protective effect of sulforaphane on ferroptosis was AMP-activated pro-tein kinase(AMPK)-dependent.These findings suggest that ferroptosis plays an essential role in the path-ogenesis 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.

Xiang Wang;Xinxin Chen;Wenqian Zhou;Hongbo Men;Terigen Bao;Yike Sun;Quanwei Wang;Yi Tan;Bradley B.Keller;Qian Tong;Yang Zheng;Lu Cai

Pediatric Research Institute,Department of Pediatrics,University of Louisville School of Medicine,Louisville,KY 40202,USA;Department of Cardiovascular Disease,the First Hospital of Jilin University,Changchun 130021,China;Department of Burn Surgery,First Hospital of Jilin University,Jilin University,Changchun 130021,China;Department of Pharmacology and Toxicology,University of Louisville School of Medicine,Louisville,KY 40202,USA;Pediatric Heart Research Program,Cardiovascular Innovation Institute,University of Louisville School of Medicine,Louisville,KY 40202,USA;Cincinnati Children's Heart Institute,Greater Louisville and Western Kentucky Practice,Louisville,KY 40202,USA

药学学报（英文版）

[1]Xiang Wang;Xinxin Chen;Wenqian Zhou;Hongbo Men;Terigen Bao;Yike Sun;Quanwei Wang;Yi Tan;Bradley B.Keller;Qian Tong;Yang Zheng;Lu Cai-.Ferroptosis is essential for diabetic cardiomyopathy and is prevented by sulforaphane via AMPK/NRF2 pathways)[J].药学学报（英文版）,2022(02):708-722

ECTs,liproxstatin,ogenesis

Ferroptosis,essential,diabetic,cardiomyopathy,prevented,by,sulforaphane,via,AMPK,NRF2,pathways,Herein,define,role,ferroptosis,pathogenesis,DCM,examining,expression,key,regulators,mice,new,vivo,Advanced,glycation,products,AGEs,important,pathogenic,were,found,engineered,cardiac,tissues,reflected,through,increased,levels,Ptgs2,lipid,peroxides,decreased,ferritin,SLC7A11,Typical,morphological,changes,cardiomyocytes,observed,using,transmission,electron,croscopy,Inhibition,ferrostatin,deferoxamine,induced,modeling,dysfunction,was,also,evidenced,type,development,diastolic,months,after,onset,diabetes,Nuclear,erythroid,related,activated,inhibited,cell,both,treated,hearts,upregulating,protective,effect,tein,kinase,dependent,These,findings,that,plays,prevents,associated,mediated,activation,This,suggests,feasible,therapeutic,approach,clinically

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