Ataxia telangiectasia mutated in cardiac fibroblasts regulates doxorubicin-induced cardiotoxicity

Aims Doxorubicin (Dox) is a potent anti-cancer agent which 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, mortality). As ATM was expressed and activated predominantly in cardiac fibroblasts, fibroblast-specific Atm-deleted mice (Atmfl/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.