Browsing by Author "Miyagawa, Kiyoshi"

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    Ataxia telangiectasia mutated in cardiac fibroblasts regulates doxorubicin-induced cardiotoxicity
    (Oxford University Press, 2016-05-01) Zhan, Hong; Aizawa, Kenichi; Sun, Junqing; Tomida, Shota; Otsu, Kinya; Conway, Simon J.; Mckinnon, Peter J.; Manabe, Ichiro; Komuro, Issei; Miyagawa, Kiyoshi; Nagai, Ryozo; Suzuki, Toru; Department of Pediatrics, School of Medicine
    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.