title: Foxo3a inhibits mitochondrial fission and protects against doxorubicin-induced cardiotoxicity by suppressing MIEF2.
abstract: Doxorubicin (DOX) as a chemotherapeutic drug is widely used to treat a variety of human tumors. However, a major factor limiting its clinical use is its cardiotoxicity. The molecular components and detailed mechanisms regulating DOX-induced cardiotoxicity remain largely unidentified. Here we report that Foxo3a is downregulated in the cardiomyocyte and mouse heart in response to DOX treatment. Foxo3a attenuates DOX-induced mitochondrial fission and apoptosis in cardiomyocytes. Cardiac specific Foxo3a transgenic mice show reduced mitochondrial fission, apoptosis and cardiotoxicity upon DOX administration. Furthermore, Foxo3a directly targets mitochondrial dynamics protein of 49kDa (MIEF2) and suppresses its expression at transcriptional level. Knockdown of MIEF2 reduces DOX-induced mitochondrial fission and apoptosis in cardiomyocytes and in vivo. Also, knockdown of MIEF2 protects heart from DOX-induced cardiotoxicity. Our study identifies a novel pathway composed of Foxo3a and MIEF2 that mediates DOX cardiotoxicity. This discovery provides a promising therapeutic strategy for the treatment of cancer therapy and cardioprotection.
authors.affiliation: Center for Developmental Cardiology, Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China.
authors.forename: Luyu
authors.initials: L
authors.lastname: Zhou
authors.affiliation: School of Professional Studies, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Ruibei
authors.initials: R
authors.lastname: Li
authors.affiliation: Center for Developmental Cardiology, Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China.
authors.forename: Cuiyun
authors.initials: C
authors.lastname: Liu
authors.affiliation: Center for Developmental Cardiology, Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China.
authors.forename: Teng
authors.initials: T
authors.lastname: Sun
authors.affiliation: College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Lynn Htet
authors.initials: LH
authors.lastname: Htet Aung
authors.affiliation: Center for Developmental Cardiology, Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Chen
authors.affiliation: Center for Developmental Cardiology, Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China.
authors.forename: Jinning
authors.initials: J
authors.lastname: Gao
authors.affiliation: Center for Developmental Cardiology, Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China.
authors.forename: Yanfang
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Center for Developmental Cardiology, Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China. Electronic address: Wangk696@qdu.edu.cn.
authors.forename: Kun
authors.initials: K
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D066126:Cardiotoxicity / Q000209:etiology / Q000235:genetics*; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects*; D000071316:Forkhead Box Protein O3 / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D063154:Mitochondrial Dynamics / Q000187:drug effects; D024101:Mitochondrial Proteins / Q000235:genetics*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D009369:Neoplasms / Q000150:complications* / Q000188:drug therapy; D010445:Peptide Elongation Factors / Q000235:genetics*
chemical_list: D000071316:Forkhead Box Protein O3; C474033:FoxO3 protein, mouse; C585230:MIEF2 protein, human; D024101:Mitochondrial Proteins; D010445:Peptide Elongation Factors; D004317:Doxorubicin
keywords: DOX cardiotoxicity; Foxo3a; MIEF2; Mitochondrial fission