Semaglutide attenuates doxorubicin-induced cardiotoxicity by ameliorating BNIP3-Mediated mitochondrial dysfunction

作者：Xiaoping Li, Wenbin Luo, Yang Tang, Jiangjiao Wu, Junkai Zhang, Shengnan Chen, Zhou Lü, Tao Yu, Yuanjuan Tang, Fengxian Wang, Yu Huang, Pedro A. José, Guo Li, Chunyu Zeng · 发表于：Redox Biology · 年份：2024 · DOI：10.1016/j.redox.2024.103129 · 被引用次数：67 · 研究领域：Chemotherapy-induced cardiotoxicity and mitigation、Cardiovascular Function and Risk Factors、Lung Cancer Research Studies

AIMS: Doxorubicin is a powerful chemotherapeutic agent for cancer, whose use is limited due to its potential cardiotoxicity. Semaglutide (SEMA), a novel analog of glucagon-like peptide-1 (GLP-1), has received widespread attention for the treatment of diabetes. However, increasing evidence has highlighted its potential therapeutic benefits on cardiac function. Therefore, the objective of this study was to examine the efficacy of semaglutide in ameliorating doxorubicin-induced cardiotoxicity. METHODS AND RESULTS: Doxorubicin-induced cardiotoxicity is an established model to study cardiac function. Cardiac function was studied by transthoracic echocardiography and invasive hemodynamic monitoring. The results showed that semaglutide significantly ameliorated doxorubicin-induced cardiac dysfunction. RNA sequencing suggested that Bnip3 is the candidate gene that impaired the protective effect of semaglutide in doxorubicin-induced cardiotoxicity. To determine the role of BNIP3 on the effect of semaglutide in doxorubicin-induced cardiotoxicity, BNIP3 with adeno-associated virus serotype 9 (AAV9) expressing cardiac troponin T (cTnT) promoter was injected into tail vein of C57/BL6J mice to overexpress BNIP3, specifically in the heart. Overexpression of BNIP3 prevented the improvement in cardiac function caused by semaglutide. In vitro experiments showed that semaglutide, via PI3K/AKT pathway, reduced BNIP3 expression in the mitochondria, improving mitochondrial function. CONCLUSION: Se...