| Autor: |
Xiaofen, Li, Jiyi, Liang, Liping, Qu, Sili, Liu, Anquan, Qin, Honglin, Liu, Tao, Wang, Wei, Li, Wenjun, Zou |
| Rok vydání: |
2022 |
| Předmět: |
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| Zdroj: |
Chemico-Biological Interactions. 363:110008 |
| ISSN: |
0009-2797 |
| DOI: |
10.1016/j.cbi.2022.110008 |
| Popis: |
Doxorubicin (DOX) is an effective antitumor drug; however, but its clinical application is seriously limited by the cardiotoxicity induced by its use. Recent studies have found that ferroptosis is an important mechanism underlying DOX-induced cardiotoxicity. However, existing studies are based on DOX-induced acute or subacute cardiotoxicity model. Therefore, we established a murine model of DOX-induced chronic cardiotoxicity using the clinically relevant cumulative dose, to evaluate the potential molecular mechanism underlying ferroptosis of cardiomycocytes. Male C57 mice were received intraperitoneal injections of DOX at a dose of 3 mg/kg body weight, once a week for 12 weeks. We dynamically analysed echocardiographic findings, serum myocardial enzyme levels, haematological indexes and cardiac histopathological changes. The results showed that, after receiving a cumulative DOX dose of 15 mg/kg, the mice developed anaemia and the function and structure of the heart changed significantly with an increase in the cumulative DOX dose. Importantly, with a cumulative DOX dose of 36 mg/kg, iron overload occurred in the heart tissue. Moreover, RNA-sequencing analysis and experimental verification revealed that ferropotosis is the underlying mechanism of DOX-induced chronic cardiotoxicity. Our results showed that DOX inhibits Slc7a11 in system-Xc, resulting in the reduction of GSH synthesis to prevent GPX4 from scavenging lipid peroxides. In addition, DOX induced the occurrence of ferroptosis via down-regulating Nrf2 expression to inhibit HO-1 and GPx4 levels. Our study provides a new perspective for evaluating the pathophysiology of DOX-induced chronic cardiotoxicity in the future, and developing new potential therapeutic strategies for the prevention and treatment of DOX-induced cardiotoxicity. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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