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

Xiaoping Li, Department of Cardiology, Daping Hospital, Third Military Medical University (Army Medical University), Chongqing, China; Key Laboratory of Geriatric Cardiovascular and Cerebrovascular Disease Research, Ministry of Education of China, Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, China.
Wenbin Luo, Department of Cardiology, Daping Hospital, Third Military Medical University (Army Medical University), Chongqing, China; Key Laboratory of Geriatric Cardiovascular and Cerebrovascular Disease Research, Ministry of Education of China, Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, China.
Yang Tang, Department of Cardiology, Daping Hospital, Third Military Medical University (Army Medical University), Chongqing, China; College of Bioengineering, Chongqing University, Chongqing, China.
Jiangjiao Wu, Department of Cardiology, Daping Hospital, Third Military Medical University (Army Medical University), Chongqing, China; Key Laboratory of Geriatric Cardiovascular and Cerebrovascular Disease Research, Ministry of Education of China, Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, China.
Junkai Zhang, Department of Cardiology, Daping Hospital, Third Military Medical University (Army Medical University), Chongqing, China; Key Laboratory of Geriatric Cardiovascular and Cerebrovascular Disease Research, Ministry of Education of China, Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, China.
Shengnan Chen, Department of Cardiology, Daping Hospital, Third Military Medical University (Army Medical University), Chongqing, China; Key Laboratory of Geriatric Cardiovascular and Cerebrovascular Disease Research, Ministry of Education of China, Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, China.
Lu Zhou, Department of Cardiology, Daping Hospital, Third Military Medical University (Army Medical University), Chongqing, China; Key Laboratory of Geriatric Cardiovascular and Cerebrovascular Disease Research, Ministry of Education of China, Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, China.
Yu Tao, Department of Cardiology, Daping Hospital, Third Military Medical University (Army Medical University), Chongqing, China; Key Laboratory of Geriatric Cardiovascular and Cerebrovascular Disease Research, Ministry of Education of China, Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, China.
Yuanjuan Tang, Department of Cardiology, Daping Hospital, Third Military Medical University (Army Medical University), Chongqing, China; Key Laboratory of Geriatric Cardiovascular and Cerebrovascular Disease Research, Ministry of Education of China, Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, China; Department of Cardiology, The Third People's Hospital of Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, Chengdu, China.
Fengxian Wang, Department of Cardiology, Daping Hospital, Third Military Medical University (Army Medical University), Chongqing, China; Key Laboratory of Geriatric Cardiovascular and Cerebrovascular Disease Research, Ministry of Education of China, Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, China.
Yu Huang, Department of Biomedical Sciences, City University of Hong Kong, Hong Kong Special Administrative Region, China.
Pedro A. Jose, Division of Renal Diseases & Hypertension, The George Washington University School of Medicine & Health Sciences, Washington, DC, USA.
Li Guo, Endocrinology Department, The First Affiliated Hospital of the Third Military Medical University (Army Medical University), Chongqing, China. Electronic address: dearpeardog@126.com.
Chunyu Zeng, Department of Cardiology, Daping Hospital, Third Military Medical University (Army Medical University), Chongqing, China; Key Laboratory of Geriatric Cardiovascular and Cerebrovascular Disease Research, Ministry of Education of China, Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, China; State Key Laboratory of Trauma, Burns and Combined Injury, Daping Hospital, Third Military Medical University, Chongqing, China; Center of Chongqing College, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Chongqing, China; Department of Cardiology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, China. Electronic address: zengchunyu@tmmu.edu.cn.

Document Type

Journal Article

Publication Date

6-1-2024

Journal

Redox biology

Volume

72

DOI

10.1016/j.redox.2024.103129

Keywords

BNIP3; Doxorubicin-induced cardiotoxicity; Mitochondria; PI3K/AKT; Semaglutide

Abstract

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: Semaglutide ameliorates doxorubicin-induced mitochondrial and cardiac dysfunction via PI3K/AKT pathway, by reducing BNIP3 expression in mitochondria. The improvement in mitochondrial function reduces doxorubicin-mediated cardiac injury and improves cardiac function. Therefore, semaglutide is a potential therapy to reduce doxorubicin-induced acute cardiotoxicity.

Department

Medicine

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