title: Identification of the molecular basis of doxorubicin-induced cardiotoxicity.
abstract: Doxorubicin is believed to cause dose-dependent cardiotoxicity through redox cycling and the generation of reactive oxygen species (ROS). Here we show that cardiomyocyte-specific deletion of Top2b (encoding topoisomerase-IIβ) protects cardiomyocytes from doxorubicin-induced DNA double-strand breaks and transcriptome changes that are responsible for defective mitochondrial biogenesis and ROS formation. Furthermore, cardiomyocyte-specific deletion of Top2b protects mice from the development of doxorubicin-induced progressive heart failure, suggesting that doxorubicin-induced cardiotoxicity is mediated by topoisomerase-IIβ in cardiomyocytes.
authors.affiliation: Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Sui
authors.initials: S
authors.lastname: Zhang
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Liu
authors.forename: Tasneem
authors.initials: T
authors.lastname: Bawa-Khalfe
authors.forename: Long-Sheng
authors.initials: LS
authors.lastname: Lu
authors.forename: Yi Lisa
authors.initials: YL
authors.lastname: Lyu
authors.forename: Leroy F
authors.initials: LF
authors.lastname: Liu
authors.forename: Edward T H
authors.initials: ET
authors.lastname: Yeh
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D054715:Cardiotoxins; D004250:DNA Topoisomerases, Type II / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D004317:Doxorubicin / Q000633:toxicity*; D006333:Heart Failure / Q000139:chemically induced; D006801:Humans; D051379:Mice; D063269:Mitochondrial Turnover / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000075223:Poly-ADP-Ribose Binding Proteins; D017382:Reactive Oxygen Species / Q000378:metabolism; D017384:Sequence Deletion
chemical_list: D054715:Cardiotoxins; D004268:DNA-Binding Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D017382:Reactive Oxygen Species; D004317:Doxorubicin; D004250:DNA Topoisomerases, Type II; C000618814:TOP2B protein, human; C000618815:Top2b protein, mouse