Tax1 banding protein 1(Tax1bp1)was originally identified as an NF-KB regulatory protein that participated in inflammatory,antiviral and Innate immune processes.Tax1 bp1 also functions as an autophagy receptor that plays a role in autophagy.Our previous study shows that Tax1 bp1 protects against cardiomyopathy in STZ-induced diabetic mice.In this study we investigated the role of Tax1bp1 in heart failure.Pressure overload-induced heart failure model was established in mice by aortic banding(AB)surgery,and angiotensin Ⅱ(Ang Ⅱ)-induced heart failure model was established by infusion of Ang Ⅱ through osmotic minipump for 4 weeks.We showed that the expression levels of Tax1bp1 in the heart were markedly increased 2 and 4 weeks after AB surgery.Knockdown of Tax1bp1 in mouse hearts significantly ameliorated both AB-and Ang Ⅱ infusion-induced heart failure parameters.On the contrary,AB-induced heart failure was aggravated in cardiac-specific Tax1bp1 transgenic mice.Similar results were observed in neonatal rat cardiomyocytes(NRCMs)under Ang Ⅱ insult.We demonstrated that the pro-heart failure effect of Tax1bp1 resulted from its interaction with the E3 ligase ITCH to promote the transcription factor P73 ubiquitination and degradation,causing enhanced BCL2 interacting protein 3(BNIP3)-mediated cardiomyocyte apoptosis.Knockdown ITCH or BNIP3 in NRCMs significantly reduced Ang Ⅱ-induced apoptosis in vitro.Similarly,BNIP3 knockdown attenuated heart failure in cardiac-specific Tax1bp1 transgenic mice.In the left ventricles of heart failure patients,Tax1 bp1 expression level was significantly increased;Tax1 bp1 gene expression was negatively correlated with left ventricular ejection fraction in heart failure patients.Collectively,the Tax1 bp1 increase in heart failure enhances ITCH-P73-BNIP3-mediated cardiomyocyte apoptosis and induced cardiac injury.Tax1 bp1 may serve as a potent therapeutic target for the treatment of heart failure.

Qing-qing Wu;Qi Yao;Tong-tong Hu;Ying Wan;Qing-wen Xie;Jin-hua Zhao;Yuan Yuan;Qi-zhu Tang

Department of Cardiology,Renmin Hospital of Wuhan University,Wuhan 430060,China;Cardiovascular Research Institute,Wuhan University,Wuhan 430060,China;Hubei Key Laboratory of Metabolic and Chronic Diseases,Wuhan 430060,China

中国药理学报（英文版）

[1]Qing-qing Wu;Qi Yao;Tong-tong Hu;Ying Wan;Qing-wen Xie;Jin-hua Zhao;Yuan Yuan;Qi-zhu Tang-.Tax1 banding protein 1 exacerbates heart failure in mice by activating ITCH-P73-BNIP3-mediated cardiomyocyte apoptosis)[J].中国药理学报（英文版）,2022(10):2562-2572

Tax1,Tax1bp1,bp1,minipump

banding,protein,exacerbates,failure,mice,by,activating,ITCH,P73,BNIP3,mediated,apoptosis,was,originally,identified,KB,regulatory,that,participated,inflammatory,antiviral,Innate,immune,processes,also,functions,autophagy,receptor,plays,role,Our,previous,study,shows,protects,against,cardiomyopathy,STZ,induced,diabetic,this,investigated,Pressure,overload,model,established,aortic,AB,surgery,angiotensin,Ang,infusion,through,osmotic,weeks,We,showed,expression,levels,were,markedly,increased,after,Knockdown,mouse,hearts,significantly,ameliorated,both,parameters,On,contrary,aggravated,cardiac,specific,transgenic,results,observed,neonatal,cardiomyocytes,NRCMs,under,insult,demonstrated,effect,resulted,from,its,interaction,E3,ligase,promote,transcription,ubiquitination,degradation,causing,enhanced,BCL2,interacting,reduced,vitro,Similarly,knockdown,attenuated,left,ventricles,patients,gene,negatively,correlated,ventricular,ejection,fraction,Collectively,enhances,injury,may,potent,therapeutic,target,treatment

0.4221