Cardiac sirtuin1 deficiency exacerbates ferroptosis in doxorubicin-induced cardiac injury through the Nrf2/Keap1 pathway.
Chem Biol Interact
; 377: 110469, 2023 May 25.
Article
em En
| MEDLINE
| ID: mdl-37030624
ABSTRACT
Doxorubicin (DOX), a broad-spectrum chemotherapeutic agent for various cancers, has limited clinical application because of its serious cardiotoxicity, which is due to different mechanisms, including cardiac ferroptosis and oxidative stress. Some drugs, such as berberine or dioscin, show efficacy in impeding DOX-induced cardiotoxicity by activating Sirtuin 1 (Sirt1). However, there is no direct evidence to clarify the role of Sirt1 in DOX-induced cardiomyopathy and its underlying role in cardiac ferroptosis. In this study, C57BL/6 and cardiac-specific Sirt1-/- knockout mice were used as a DOX-induced cardiotoxicity model. We found that cardiac Sirt1 was downregulated, oxidative stress was increased and ferroptosis were obviously enhanced, as reflected by decreased Glutathione peroxidase 4 (GPX4) and increased Heme oxygenase 1 (Hmox-1), exposure to DOX treatment in mice and H9c2 cells compared with the control. And Sirt1 activation was resistant to cardiac injury induced by DOX, as observed the improvement of cardiac dysfunction, and the reduction of cardiac fibrosis. However, cardiac Sirt1 deficiency aggravated Dox-induced cardiac dysfunction and cardiac remodeling, further downregulated GPX4, upregulated Hmox-1 expression and increased ROS level. In addition, Sirt1-siRNA exacerbated DOX-induced cardiotoxicity in H9c2 cells, which is similar to the results obtained in vivo. Furthermore, DOX decrease Nrf2 translocation from the cytosol to the nucleus, and Sirt1 deficiency further restrain the process, as well as the downstream Keap1 pathways, in DOX-induced cardiotoxicity. This study provides direct evidence that Sirt1 plays a protective role in DOX-induced cardiotoxicity by mediating ferroptosis reduction via the Nrf2/Keap1 pathway.
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Texto completo:
1
Coleções:
01-internacional
Temas:
Geral
Base de dados:
MEDLINE
Assunto principal:
Ferroptose
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Cardiopatias
/
Traumatismos Cardíacos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Chem Biol Interact
Ano de publicação:
2023
Tipo de documento:
Article