Ataxia telangiectasia mutated in cardiac fibroblasts regulates doxorubicin-induced cardiotoxicity

作者：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^*

来源：Cardiovascular Research, 2016, 110(1): 85-95.

DOI：10.1093/cvr/cvw032

• Doxorubicin
• Ataxia telangiectasia mutated
• Cardiac fibroblasts
• Doxorubicin-induced cardiotoxicity

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.
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.
ATM-regulated effects within cardiac fibroblasts are pivotal in Dox-induced cardiotoxicity, and antagonism of ATM and its functions may have potential therapeutic implications.

• 出版日期2016-5-1
• 单位西安交通大学