Ataxia telangiectasia mutated in cardiac fibroblasts regulates doxorubicin-induced cardiotoxicity

Hong Zhan, Kenichi Aizawa, Junqing Sun, Shota Tomida, Kinya Otsu, Simon J. Conway, Peter J. McKinnon, Ichiro Manabe, Issei Komuro, Kiyoshi Miyagawa, Ryozo Nagai, Toru Suzuki

Research output: Contribution to journalArticle

26 Scopus citations

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 (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.

Original languageEnglish (US)
Pages (from-to)85-95
Number of pages11
JournalCardiovascular research
Volume110
Issue number1
DOIs
StatePublished - May 1 2016

Keywords

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

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    Zhan, H., Aizawa, K., Sun, J., Tomida, S., Otsu, K., Conway, S. J., McKinnon, P. J., Manabe, I., Komuro, I., Miyagawa, K., Nagai, R., & Suzuki, T. (2016). Ataxia telangiectasia mutated in cardiac fibroblasts regulates doxorubicin-induced cardiotoxicity. Cardiovascular research, 110(1), 85-95. https://doi.org/10.1093/cvr/cvw032