Loss of TRIM21 alleviates cardiotoxicity by suppressing ferroptosis induced by the chemotherapeutic agent doxorubicin

EBioMedicine

Chuannan Zhai¹  Yaping Jiang¹  Jianliang Shen²  Junrong Yan³  Richard Z. Lin⁴  Yongbo Wang⁵  Wei-Xing Zong⁶  Ji-An Pan⁷  Jingxia Zhang⁷  Shenglan Gao⁸  Ye Zhang⁹  Kai Hou⁹  Hongliang Cong^1,10 

[1] Department of Cardiology, Tianjin Chest Hospital, Tianjin, China;Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China;Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ, USA;Department of Biochemistry and Molecular Cell Biology, School of Medicine, Sun Yat-sen University, Shenzhen, China;Department of Cardiology, Tianjin Chest Hospital, Tianjin, China;Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China;Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ, USA;Department of Physiology and Biophysics, Stony Brook University, Stony Brook, NY, USA;School of Medicine, Nankai University, Tianjin, China;Tianjin Third Central Hospital, Tianjin, China;

关键词: TRIM21;    Antioxidant;    Doxorubicin;    Cardiotoxicity;    Ferroptosis;   

DOI  :  

来源: DOAJ

【 摘 要 】

Background: Doxorubicin, 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. Methods: Using 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. Findings: TRIM21 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. Interpretation: Our 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.

【 授权许可】

Unknown