Zhan, HongAizawa, KenichiSun, JunqingTomida, ShotaOtsu, KinyaConway, Simon J.Mckinnon, Peter J.Manabe, IchiroKomuro, IsseiMiyagawa, KiyoshiNagai, RyozoSuzuki, Toru2017-08-252017-08-252016-05-01Zhan, H., Aizawa, K., Sun, J., Tomida, S., Otsu, K., Conway, S. J., … Suzuki, T. (2016). Ataxia telangiectasia mutated in cardiac fibroblasts regulates doxorubicin-induced cardiotoxicity. Cardiovascular Research, 110(1), 85–95. http://doi.org/10.1093/cvr/cvw032https://hdl.handle.net/1805/13925AIMS: 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.en-USPublisher PolicyAtaxia telangiectasia mutatedCardiac fibroblastsDoxorubicinDoxorubicin-induced cardiotoxicityArticle