Loss of TRIM21 alleviates cardiotoxicity by suppressing ferroptosis induced by the chemotherapeutic agent doxorubicin
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 in...
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| Format: | Article |
| Language: | English |
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Elsevier
2021-07-01
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| Series: | EBioMedicine |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396421002498 |
| _version_ | 1819027974599475200 |
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| author | Kai Hou Jianliang Shen Junrong Yan Chuannan Zhai Jingxia Zhang Ji-An Pan Ye Zhang Yaping Jiang Yongbo Wang Richard Z. Lin Hongliang Cong Shenglan Gao Wei-Xing Zong |
| author_facet | Kai Hou Jianliang Shen Junrong Yan Chuannan Zhai Jingxia Zhang Ji-An Pan Ye Zhang Yaping Jiang Yongbo Wang Richard Z. Lin Hongliang Cong Shenglan Gao Wei-Xing Zong |
| author_sort | Kai Hou |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-21T05:51:00Z |
| format | Article |
| id | doaj.art-b1cffd1db963412989fa3db923dcbdbf |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-12-21T05:51:00Z |
| publishDate | 2021-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-b1cffd1db963412989fa3db923dcbdbf2022-12-21T19:13:59ZengElsevierEBioMedicine2352-39642021-07-0169103456Loss of TRIM21 alleviates cardiotoxicity by suppressing ferroptosis induced by the chemotherapeutic agent doxorubicinKai Hou0Jianliang Shen1Junrong Yan2Chuannan Zhai3Jingxia Zhang4Ji-An Pan5Ye Zhang6Yaping Jiang7Yongbo Wang8Richard Z. Lin9Hongliang Cong10Shenglan Gao11Wei-Xing Zong12School of Medicine, Nankai University, 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 Cardiology, Tianjin Chest Hospital, Tianjin, ChinaDepartment of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ, USADepartment of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ, USASchool of Medicine, Nankai University, Tianjin, China; Department of Cardiology, Tianjin Chest Hospital, Tianjin, ChinaDepartment of Cardiology, Tianjin Chest Hospital, Tianjin, ChinaDepartment of Biochemistry and Molecular Cell Biology, School of Medicine, Sun Yat-sen University, Shenzhen, ChinaTianjin Third Central Hospital, Tianjin, ChinaDepartment of Physiology and Biophysics, Stony Brook University, Stony Brook, NY, USADepartment of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, ChinaDepartment of Physiology and Biophysics, Stony Brook University, Stony Brook, NY, USASchool of Medicine, Nankai University, Tianjin, China; Department of Cardiology, Tianjin Chest Hospital, Tianjin, China; Corresponding author.Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China; Corresponding author.Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ, USA; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA; Corresponding author.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.http://www.sciencedirect.com/science/article/pii/S2352396421002498TRIM21AntioxidantDoxorubicinCardiotoxicityFerroptosis |
| spellingShingle | Kai Hou Jianliang Shen Junrong Yan Chuannan Zhai Jingxia Zhang Ji-An Pan Ye Zhang Yaping Jiang Yongbo Wang Richard Z. Lin Hongliang Cong Shenglan Gao Wei-Xing Zong Loss of TRIM21 alleviates cardiotoxicity by suppressing ferroptosis induced by the chemotherapeutic agent doxorubicin EBioMedicine TRIM21 Antioxidant Doxorubicin Cardiotoxicity Ferroptosis |
| title | Loss of TRIM21 alleviates cardiotoxicity by suppressing ferroptosis induced by the chemotherapeutic agent doxorubicin |
| title_full | Loss of TRIM21 alleviates cardiotoxicity by suppressing ferroptosis induced by the chemotherapeutic agent doxorubicin |
| title_fullStr | Loss of TRIM21 alleviates cardiotoxicity by suppressing ferroptosis induced by the chemotherapeutic agent doxorubicin |
| title_full_unstemmed | Loss of TRIM21 alleviates cardiotoxicity by suppressing ferroptosis induced by the chemotherapeutic agent doxorubicin |
| title_short | Loss of TRIM21 alleviates cardiotoxicity by suppressing ferroptosis induced by the chemotherapeutic agent doxorubicin |
| title_sort | loss of trim21 alleviates cardiotoxicity by suppressing ferroptosis induced by the chemotherapeutic agent doxorubicin |
| topic | TRIM21 Antioxidant Doxorubicin Cardiotoxicity Ferroptosis |
| url | http://www.sciencedirect.com/science/article/pii/S2352396421002498 |
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