title: Ataxia telangiectasia mutated in cardiac fibroblasts regulates doxorubicin-induced cardiotoxicity.
abstract: OBJECTIVE
  Doxorubicin (Dox) is a potent anticancer agent that is widely used in the treatment of a variety of cancers, but its usage is limited by cumulative dose-dependent cardiotoxicity mainly due to oxidative damage. Ataxia telangiectasia mutated (ATM) kinase is thought to play a role in mediating the actions of oxidative stress. Here, we show that ATM in cardiac fibroblasts is essential for Dox-induced cardiotoxicity.
  
  
  RESULTS
  ATM knockout mice showed attenuated Dox-induced cardiotoxic effects (e.g. cardiac dysfunction, apoptosis, and mortality). As ATM was expressed and activated predominantly in cardiac fibroblasts, fibroblast-specific Atm-deleted mice (Atm(fl/fl);Postn-Cre) were generated to address cell type-specific effects, which showed that the fibroblast is the key lineage mediating Dox-induced cardiotoxicity through ATM. Mechanistically, ATM activated the Fas ligand, which subsequently regulated apoptosis in cardiomyocytes at later stages. Therapeutically, a potent and selective inhibitor of ATM, KU55933, when administered systemically was able to prevent Dox-induced cardiotoxicity.
  
  
  CONCLUSIONS
  ATM-regulated effects within cardiac fibroblasts are pivotal in Dox-induced cardiotoxicity, and antagonism of ATM and its functions may have potential therapeutic implications.
authors: Jichi Medical University, Tochigi, Japan Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors: Hong
authors: H
authors: Zhan
authors: Jichi Medical University, Tochigi, Japan Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors: Kenichi
authors: K
authors: Aizawa
authors: Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan The Key Laboratory of Biomedical Information Engineering, Xi'an Jiaotong University, Xi'an, China.
authors: Junqing
authors: J
authors: Sun
authors: Jichi Medical University, Tochigi, Japan Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors: Shota
authors: S
authors: Tomida
authors: Cardiovascular Division, King's College London, London, UK.
authors: Kinya
authors: K
authors: Otsu
authors: Program in Developmental Biology and Neonatal Medicine, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA.
authors: Simon J
authors: SJ
authors: Conway
authors: Department of Genetics, St Jude Children's Research Hospital, Memphis, TN, USA.
authors: Peter J
authors: PJ
authors: Mckinnon
authors: Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors: Ichiro
authors: I
authors: Manabe
authors: Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors: Issei
authors: I
authors: Komuro
authors: Department of Radiation Biology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors: Kiyoshi
authors: K
authors: Miyagawa
authors: Jichi Medical University, Tochigi, Japan.
authors: Ryozo
authors: R
authors: Nagai
authors: Jichi Medical University, Tochigi, Japan Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan Department of Cardiovascular Sciences, University of Leicester Cardiovascular Research Centre, University of Leicester, Glenfield Hospital Groby Road, Glenfield, Leicester LE3 9QP, UK National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK ts263@le.ac.uk torusuzu-tky@umin.ac.jp.
authors: Toru
authors: T
authors: Suzuki
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001260:Ataxia Telangiectasia / Q000235:genetics*; D066126:Cardiotoxicity / Q000209:etiology*; D004317:Doxorubicin / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects*; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000187:drug effects*; D018384:Oxidative Stress / Q000187:drug effects
chemical_list: D004317:Doxorubicin
keywords: Ataxia telangiectasia mutated; Cardiac fibroblasts; Doxorubicin; Doxorubicin-induced cardiotoxicity