Hong Zhan1, Kenichi Aizawa1, Junqing Sun2, Shota Tomida1, Kinya Otsu3, Simon J Conway4, Peter J Mckinnon5, Ichiro Manabe6, Issei Komuro6, Kiyoshi Miyagawa7, Ryozo Nagai8, Toru Suzuki9. 1. Jichi Medical University, Tochigi, Japan Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. 2. 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. 3. Cardiovascular Division, King's College London, London, UK. 4. Program in Developmental Biology and Neonatal Medicine, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA. 5. Department of Genetics, St Jude Children's Research Hospital, Memphis, TN, USA. 6. Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. 7. Department of Radiation Biology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. 8. Jichi Medical University, Tochigi, Japan. 9. 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.
Abstract
AIMS: 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. METHODS AND 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. CONCLUSION: ATM-regulated effects within cardiac fibroblasts are pivotal in Dox-induced cardiotoxicity, and antagonism of ATM and its functions may have potential therapeutic implications. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: 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. METHODS AND 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. CONCLUSION:ATM-regulated effects within cardiac fibroblasts are pivotal in Dox-induced cardiotoxicity, and antagonism of ATM and its functions may have potential therapeutic implications. Published on behalf of the European Society of Cardiology. All rights reserved.
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