Alzheimer's disease(AD)is associated with high incidence of cardiovascular events but the mechanism remains elusive.Our previous study reveals a tight correlation between cardiac dysfunction and low mitochondrial aldehyde dehydrogenase(ALDH2)activity in elderly AD patients.In the present study we investigated the effect of ALDH2 overexpression on cardiac function in APP/PS1 mouse model of AD.Global ALDH2 transgenic mice were crossed with APP/PS1 mutant mice to generate the ALDH2-APP/PS1 mutant mice.Cognitive function,cardiac contractile,and morphological properties were assessed.We showed that APP/PS1 mice displayed significant cognitive deficit in Morris water maze test,myocardial ultrastructural,geometric(cardiac atrophy,interstitial fibrosis)and functional(reduced fractional shortening and cardiomyocyte contraction)anomalies along with oxidative stress,apoptosis,and inflammation in myocardium.ALDH2 transgene significantly attenuated or mitigated these anomalies.We also noted the markedly elevated levels of lipid peroxidation,the essential lipid peroxidation enzyme acyl-CoA synthetase long-chain family member 4(ACSL4),the transcriptional regulator for ACLS4 special protein 1(SP1)and ferroptosis,evidenced by elevated NCOA4,decreased GPx4,and SLC7A11 in myocardium of APP/PS1 mutant mice;these effects were nullified by ALDH2 transgene.In cardiomyocytes isolated from WT mice and in H9C2 myoblasts in vitro,application of Aβ(20 μM)decreased cell survival,compromised cardiomyocyte contractile function,and induced lipid peroxidation;ALDH2 transgene or activator Alda-1 rescued Aβ-induced deteriorating effects.ALDH2-induced protection against Aβ-induced lipid peroxidation was mimicked by the SP1 inhibitor tolfenamic acid(TA)or the ACSL4 inhibitor triacsin C(TC),and mitigated by the lipid peroxidation inducer 5-hydroxyeicosatetraenoic acid(5-HETE)or the ferroptosis inducer erastin.These results demonstrate an essential role for ALDH2 in AD-induced cardiac anomalies through regulation of lipid peroxidation and ferroptosis.

Zhi-yun Zhu;Yan-dong Liu;Yan Gong;Wei Jin;Elena Topchiy;Subat Turdi;Yue-feng Gao;Bruce Culver;Shu-yi Wang;Wei Ge;Wen-liang Zha;Jun Ren;Zhao-hui Pei;Xing Qin

Jiangxi Provincial People's Hospital Affiliated to Nanchang University,Nanchang 330006,China;The Second Department of Cardiology,The Third Hospital of Nanchang,Nanchang 330009,China;University of Wyoming College of Health Sciences,Laramie,WY,USA;State Key Laboratory of Animal Nutrition,College of Animal Science and Technology,China Agricultural University,Beijing 100083,China;Department of General Practice,Xijing Hospital,the Air Force Military Medical University,Xi'an 710032,China;Department of Surgery,Clinic Medical College,Hubei University of Science and Technology,Xianning 437100,China;National Demonstration Center for Experimental General Medicine Education,Hubei University of Science and Technology,Xianning 437100,China;Department of Cardiology and Shanghai Institute of Cardiovascular Diseases,Zhongshan Hospital Fudan University,Shanghai 200032,China;Department of Cardiology,Xijing Hospital,the Air Force Military Medical University,Xi'an 710032,China

中国药理学报（英文版）

[1]Zhi-yun Zhu;Yan-dong Liu;Yan Gong;Wei Jin;Elena Topchiy;Subat Turdi;Yue-feng Gao;Bruce Culver;Shu-yi Wang;Wei Ge;Wen-liang Zha;Jun Ren;Zhao-hui Pei;Xing Qin-.Mitochondrial aldehyde dehydrogenase(ALDH2)rescues cardiac contractile dysfunction in an APP/PS1 murine model of Alzheimer's disease via inhibition of ACSL4-dependent ferroptosis)[J].中国药理学报（英文版）,2022(01):39-49

ACLS4,nullified,tolfenamic,triacsin

Mitochondrial,aldehyde,dehydrogenase,ALDH2,rescues,cardiac,contractile,dysfunction,PS1,murine,model,Alzheimer,disease,via,inhibition,ACSL4,dependent,ferroptosis,AD,associated,high,incidence,cardiovascular,events,but,mechanism,remains,elusive,Our,previous,study,reveals,tight,correlation,between,low,mitochondrial,activity,elderly,patients,In,present,investigated,overexpression,mouse,Global,transgenic,mice,were,crossed,mutant,generate,Cognitive,morphological,properties,assessed,We,showed,that,displayed,cognitive,deficit,Morris,water,maze,test,myocardial,ultrastructural,geometric,atrophy,interstitial,fibrosis,functional,reduced,fractional,shortening,contraction,anomalies,along,oxidative,stress,apoptosis,inflammation,myocardium,transgene,significantly,attenuated,mitigated,these,also,noted,markedly,elevated,levels,lipid,peroxidation,essential,enzyme,acyl,CoA,synthetase,chain,family,member,transcriptional,regulator,special,protein,SP1,evidenced,by,NCOA4,decreased,GPx4,SLC7A11,effects,cardiomyocytes,isolated,from,WT,H9C2,myoblasts,vitro,application,cell,survival,compromised,induced,activator,Alda,rescued,deteriorating,protection,against,was,mimicked,inhibitor,acid,TA,inducer,hydroxyeicosatetraenoic,HETE,erastin,These,results,demonstrate,role,through,regulation

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