阿霉素
心脏毒性
基因剔除小鼠
蒽环类
癌症研究
小发夹RNA
泛素连接酶
氧化应激
药理学
KEAP1型
程序性细胞死亡
化学
细胞凋亡
细胞生物学
基因敲除
生物
医学
泛素
毒性
化疗
癌症
转录因子
生物化学
内科学
受体
乳腺癌
基因
作者
Kai Hou,Haifa Shen,Junrong Yan,Chuannan Zhai,Jingxia Zhang,Jian Pan,Ye Zhang,Ya-Ping Jiang,Yong Wang,Richard Z. Lin,Hongliang Cong,Shenglan Gao,Wei-Xing Zong
出处
期刊:EBioMedicine
[Elsevier]
日期:2021-07-01
卷期号:69: 103456-103456
被引量:39
标识
DOI:10.1016/j.ebiom.2021.103456
摘要
BackgroundDoxorubicin, an anthracycline chemotherapeutic agent, is widely used in the treatment of many cancers. However, doxorubicin posts a great risk of adverse cardiovascular events, which are thought to be caused by oxidative stress. We recently reported that the ubiquitin E3 ligase TRIM21 interacts and ubiquitylates p62 and negatively regulates the p62-Keap1-Nrf2 antioxidant pathway. Therefore, we sought to determine the role TRIM21 in cardiotoxicity induced by oxidative damage.MethodsUsing TRIM21 knockout mice, we examined the effects of TRIM21 on cardiotoxicity induced by two oxidative damage models: the doxorubicin treatment model and the Left Anterior Descending (LAD) model. We also explored the underlying mechanism by RNA-sequencing of the heart tissues, and by treating the mouse embryonic fibroblasts (MEFs), immortalized rat cardiomyocyte line H9c2, and immortalized human cardiomyocyte line AC16 with doxorubicin.FindingsTRIM21 knockout mice are protected from heart failure and fatality in both the doxorubicin and LAD models. Hearts of doxorubicin-treated wild-type mice exhibit deformed mitochondria and elevated level of lipid peroxidation reminiscent of ferroptosis, which is alleviated in TRIM21 knockout hearts. Mechanistically, TRIM21-deficient heart tissues and cultured MEFs and H9c2 cells display enhanced p62 sequestration of Keap1 and are protected from doxorubicin-induced ferroptosis. Reconstitution of wild-type but not the E3 ligase-dead and the p62 binding-deficient TRIM21 mutants impedes the protection from doxorubicin-induced cell death.InterpretationOur study demonstrates that TRIM21 ablation protects doxorubicin-induced cardiotoxicity and illustrates a new function of TRIM21 in ferroptosis, and suggests TRIM21 as a therapeutic target for reducing chemotherapy-related cardiotoxicity.FundingNIH (CA129536; DK108989): data collection, analysis.Shanghai Pujiang Program (19PJ1401900): data collection.National Natural Science Foundation (31971161): data collection.Department of Veteran Affairs (BX004083): data collection.Tianjin Science and Technology Plan Project (17ZXMFSY00020): data collection.
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