Semaglutide attenuates doxorubicin-induced cardiotoxicity by ameliorating BNIP3-Mediated mitochondrial dysfunction
Xiaoping Li,
Wenbin Luo,
Yang Tang,
Jiangjiao Wu,
Junkai Zhang,
Shengnan Chen,
Lu Zhou,
Yu Tao,
Yuanjuan Tang,
Fengxian Wang,
Yu Huang,
Pedro A. Jose,
Li Guo,
Chunyu Zeng
Affiliations
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
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
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; Corresponding author.
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; Corresponding author. Department of Cardiology, Daping Hospital, Third Military Medical University (Army Medical University), Chongqing, China.
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.
