Modeling drug-induced mitochondrial toxicity with human primary cardiomyocytes
作者机构:State Key Laboratory of Cardiovascular DiseaseFuwai HospitalNational Center for Cardiovascular DiseasesChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100037China Department of EpidemiologyCardiovascular Institute and Fuwai HospitalChinese Academy of Medical Science&Peking Union Medical CollegeBeijing 100037China Shenzhen Key Laboratory of Cardiovascular DiseaseFuwai Hospital Chinese Academy of Medical SciencesShenzhenShenzhen 518020China
出 版 物:《Science China(Life Sciences)》 (中国科学(生命科学英文版))
年 卷 期:2024年第67卷第2期
页 面:301-319页
核心收录:
学科分类:0710[理学-生物学] 1007[医学-药学(可授医学、理学学位)] 1006[医学-中西医结合] 100706[医学-药理学] 100602[医学-中西医结合临床] 10[医学]
基 金:supported by the CAMS Innovation Fund for Medical Sciences(CIFMS)(2021-1-I2M-006,2023-I2M-1-003,2022-I2M-2-001,2021-1-I2M-019) the National Natural Science Foundation of China(82070287,82088101 and 82025004) the National Key Research and Development Program of China(2022YFA1104500)
主 题:remdesivir mitochondrial toxicity cardiotoxicity human primary cardiomyocytes high-throughput screening
摘 要:Mitochondrial toxicity induced by therapeutic drugs is a major contributor for cardiotoxicity,posing a serious threat to pharmaceutical industries and patients’***,mitochondrial toxicity testing is not incorporated into routine cardiac safety screening *** accurately model native human cardiomyocytes,we comprehensively evaluated mitochondrial responses of adult human primary cardiomyocytes(h PCMs)to a nucleoside analog,remdesivir(RDV).Comparison of their response to human pluripotent stem cell-derived cardiomyocytes revealed that the latter utilized a mitophagy-based mitochondrial recovery response that was absent in h ***,action potential duration was elongated in h PCMs,reflecting clinical incidences of RDV-induced QT *** a screen for mitochondrial protectants,we identified mitochondrial ROS as a primary mediator of RDV-induced *** study demonstrates the utility of h PCMs in the detection of clinically relevant cardiac toxicities,and offers a framework for h PCM-based high-throughput screening of cardioprotective agents.