Cardiomyocyte-specific knockout of ADAM17 alleviates doxorubicin-induced cardiomyopathy via inhibiting TNFα-TRAF3-TAK1-MAPK axis  

作　　者：Lin Xie Fei Xue Cheng Cheng Wenhai Sui Jie Zhang Linlin Meng Yue Lu Wenjing Xiong Peili Bu Feng Xu Xiao Yu Bo Xi Lin Zhong Jianmin Yang Cheng Zhang Yun Zhang 

机构地区：[1]State Key Laboratory for Innovation and Transformation of Luobing Theory,Key Laboratory of Cardiovascular Remodeling and Function Research,Chinese Ministry of Education,Chinese National Health Commission and Chinese Academy of Medical Sciences,Department of Cardiology,Qilu Hospital of Shandong University,Jinan,China [2]Department of Cardiology,Shengjing Hospital of China Medical University,Shenyang,Liaoning Province,China [3]Department of Emergency Medicine,Chest Pain Center,Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine,Qilu Hospital,Shandong University,Jinan,China [4]Key Laboratory Experimental Teratology of the Ministry of Education,Department of Physiology,School of Basic Medical Sciences,Cheeloo College of Medicine,Shandong University,Jinan,China [5]Department of Epidemiology,School of Public Health,Cheeloo College of Medicine,Shandong University,Jinan,China [6]Department of Cardiology,The Affiliated Yantai Yuhuangding Hospital of Qingdao University,Yantai,China [7]Cardiovascular Disease Research Center of Shandong First Medical University,Central Hospital Affiliated to Shandong First Medical University,Jinan,China

出　　处：《Signal Transduction and Targeted Therapy》2024年第11期5217-5236,共20页信号转导与靶向治疗（英文）

基　　金：supported by grants of the National Natural Science Foundation of China(Nos.82000411,82030051,82241203,81920108003 and 81970366);State Key R&D Program of China(2021YFF0501403);Key R&D Program of Shandong Province(2021SFGC0503,2021ZLGX02,2021ZDSYS05,2020ZLYS05);Shandong Provincial Natural Science Foundation(ZR2020QH023);the Taishan Scholars Program of Shandong Province(C.Z.);China Postdoctoral Science Foundation(2023M742124);Postdoctoral Innovation Talents Support Program(BX20230210).

摘　　要：The pathogenesis of doxorubicin-induced cardiomyopathy remains unclear.This study was carried out to test our hypothesis that ADAM17 aggravates cardiomyocyte apoptosis induced by doxorubicin and inhibition of ADAM17 may ameliorate doxorubicininduced cardiomyopathy.C57BL/6J mice were intraperitoneally injected with a cumulative dose of doxorubicin to induce cardiomyopathy.Cardiomyocyte-specific ADAM17-knockout(A17^(α-MHCKO))and ADAM17-overexpressing(AAV9-oeA17)mice were generated.In addition,RNA sequencing of the heart tissues in different mouse groups and in vitro experiments in neonatal rat cardiomyocytes(NRCMs)receiving different treatment were performed.Mouse tumor models were constructed in A17^(fl/fl )and A17α-MHCKO mice.In addition,cardiomyocyte-specific TRAF3-knockdown and TRAF3-overexpressing mice were generated.ADAM17 expression and activity were markedly upregulated in doxorubicin-treated mouse hearts and NRCMs.A17^(α-MHCKO) mice showed less cardiomyocyte apoptosis induced by doxorubicin than A17^(fl/fl) mice,and cardiomyocyte ADAM17 deficiency did not affect the anti-tumor effect of doxorubicin.In contrast,AAV9-oeA17 mice exhibited markedly aggravated cardiomyocyte apoptosis relative to AAV9-oeNC mice after doxorubicin treatment.Mechanistically,doxorubicin enhanced the expression of transcription factor C/EBPβ,leading to increased expression and activity of ADAM17 in cardiomyocyte,which enhanced TNF-αshedding and upregulated the expression of TRAF3.Increased TRAF3 promoted TAK1 autophosphorylation,resulting in activated MAPKs pathway and cardiomyocyte apoptosis.ADAM17 acted as a positive regulator of cardiomyocyte apoptosis and cardiac remodeling and dysfunction induced by doxorubicin by upregulating TRAF3/TAK1/MAPKs signaling.Thus,targeting ADAM17/TRAF3/TAK1/MAPKs signaling holds a promising potential for treating doxorubicin-induced cardiotoxicity.

关 键 词：DOXORUBICIN CARDIOMYOPATHY markedly 

分 类 号：R542.2[医药卫生—心血管疾病]