TRADD-mediated pyroptosis contributes to diabetic cardiomyopathy  

作　　者：Yang-yang Zheng Dan-ning Shen Xiao-lu Peng Wen-qing San Qian-you Zhou Sheng-ju Yang Guo-liang Meng Jia-hai Shi Yun Chen 

机构地区：[1]Department of Pharmacology,School of Pharmacy,Nantong University,Nantong,226001,China [2]Department of Pharmacy,Xuzhou Oriental Hospital Affiliated to Xuzhou Medical University,Xuzhou,221004,China [3]School of Medicine,Nantong University,Nantong,226001,China [4]Department of Thoracic Surgery,Affiliated Hospital of Nantong University,Nantong,226006,China

出　　处：《Acta Pharmacologica Sinica》2025年第4期940-950,共11页中国药理学报(英文版)

基　　金：supported by the National Natural Science Foundation of China(82200313,82070280,82270418,82370253);the“333 Project”of Jiangsu Province(2022-3-16-670);the Six Talent Peaks Project in Jiangsu Province(2018-WSN-062);Jiangsu Provincial Research Hospital(YJXYY202204);Innovation Team Project of Affiliated Hospital of Nantong University(XNBHCX31773).

摘　　要：Regulated cell death like pyroptosis is one vital cause of diabetic cardiomyopathy(DCM),which eventually leads to heart failure.Tumor necrosis factor(TNF)receptor-associated death domain protein(TRADD)is an adapter protein with multiple functions that participates in the pathophysiological progress of different cardiovascular disorders via regulating regulated cell death.Studies have shown that TRADD combines with receptor-interacting protein kinase 3(RIPK3)and facilitates its activation,thereby mediating TNF-induced necroptosis.However,no direct relationship between TRADD and pyroptosis has been identified.In this study,we investigated the role and mechanisms of TRADD in pyroptosis during DCM.We established a streptozotocin(STZ)-induced diabetic mouse model and high glucose(HG)-treated cardiomyocytes model.We showed that the expression levels of TRADD were significantly increased in the hearts of diabetic mice and HG-treated cardiomyocytes.Knockdown of TRADD did not affect blood glucose and triglyceride levels,but significantly improved cardiac function,and attenuated myocardial hypertrophy,fibrosis,and pyroptosis in the heart of diabetic mice.Furthermore,both knockdown of TRADD and application of TRADD inhibitor apostatin-1(Apt-1,10μM)significantly ameliorated cell injury and pyroptosis in HG-treated cardiomyocytes.We demonstrated that HG treatment increased the expression of X-box binding protein 1(XBP1)and enhanced the binding of XBP1 to the TRADD promoter to elevate TRADD expression in the cardiomyocytes.Collectively,this study provides evidence that TRADD-mediated pyroptosis contributes to DCM,suggesting that strategies to inhibit TRADD activity may be a novel approach for DCM treatment.

关 键 词：diabetic cardiomyopathy PYROPTOSIS TRADD XBP1 Apostatin-1 CARDIOMYOCYTE 

分 类 号：R587.2[医药卫生—内分泌]