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The mechanism of rh-endostatin-induced cardiotoxicity and its protection by dihydromyricetin[in vivo/in vitro, C57BL/6 mice, AC16 and hiPSC-CMs

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机构： [1]School of Basic Medicine, Qingdao University, Qingdao 266071, China [2]College of Pharmacy, Binzhou Medical University, Yantai 264003, China [3]Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology of Ministry of Education, Institute of Cardiovascular Research, Nucleic Acid Medicine of Luzhou Key Laboratory, Metabolic Vascular Disease Key Laboratory of Sichuan Province, Southwest Medical University, Luzhou 646000, China [4]Shandong Simcere Bio-Pharmaceutical Co., Ltd, Yantai 264006, China [5]School of Medical Imaging, Binzhou Medical University, Yantai 264003, China

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Recombinant human endostatin (rh-endostatin) is an anti-angiogenic drug, which is used for the treatment of advanced non-small-cell lung cancer (NSCLC) and other cancers. However, its side effects, especially the cardiotoxicity with unclear mechanisms limit its wide application in clinical practice. In this study, human cardiomyocyte cell line AC16 and human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) treated with different doses of rh-endostatin were used to analyze its effect on cardiac cell toxicity. The results revealed that rh-endostatin dose-dependently enhanced cardiomyocyte apoptosis through Apaf-1 apoptotic factor and apoptosis-related proteins such as p53. rh-endostatin-induced changes of mitochondrial function and mitophagy were involved in rh-endostatin-mediated cardiac cell toxicity. Rh-endostatin-induced cardiotoxicity was further verified in vivo in mice. Interestingly, Rh-endostatin-induced cardiotoxicity was inhibited by dihydromyricetin (DHM) both in cultured cells in vitro and in mouse hearts in vivo. The study provides new inside into rh-endostatin-induced cardiotoxicity and identified a novel potential medication DHM to overcome the serious adverse effect.Copyright © 2023 Elsevier B.V. All rights reserved.

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出版当年[2023]版：

大类 | 3 区医学

小类 | 3 区毒理学

最新[2023]版：

大类 | 3 区医学

小类 | 3 区毒理学

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第一作者机构： [1]School of Basic Medicine, Qingdao University, Qingdao 266071, China

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通讯机构： [2]College of Pharmacy, Binzhou Medical University, Yantai 264003, China [3]Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology of Ministry of Education, Institute of Cardiovascular Research, Nucleic Acid Medicine of Luzhou Key Laboratory, Metabolic Vascular Disease Key Laboratory of Sichuan Province, Southwest Medical University, Luzhou 646000, China [*1]College of Pharmacy, Binzhou Medical University, Yantai 264003, China.

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