Ataxia telangiectasia mutated in cardiac fibroblasts regulates doxorubicin-induced cardiotoxicity

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

Research output: Contribution to journalArticle

19 Citations (Scopus)

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

Fingerprint

Ataxia Telangiectasia
Doxorubicin
Fibroblasts
Apoptosis
Cardiotoxicity
Fas Ligand Protein
Cardiac Myocytes
Knockout Mice
Antineoplastic Agents
Oxidative Stress
Phosphotransferases
Mortality

Keywords

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

ASJC Scopus subject areas

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

Cite this

Ataxia telangiectasia mutated in cardiac fibroblasts regulates doxorubicin-induced cardiotoxicity. / Zhan, Hong; Aizawa, Kenichi; Sun, Junqing; Tomida, Shota; Otsu, Kinya; Conway, Simon; McKinnon, Peter J.; Manabe, Ichiro; Komuro, Issei; Miyagawa, Kiyoshi; Nagai, Ryozo; Suzuki, Toru.

In: Cardiovascular Research, Vol. 110, No. 1, 01.05.2016, p. 85-95.

Research output: Contribution to journalArticle

Zhan, H, Aizawa, K, Sun, J, Tomida, S, Otsu, K, Conway, S, McKinnon, PJ, Manabe, I, Komuro, I, Miyagawa, K, Nagai, R & Suzuki, T 2016, 'Ataxia telangiectasia mutated in cardiac fibroblasts regulates doxorubicin-induced cardiotoxicity', Cardiovascular Research, vol. 110, no. 1, pp. 85-95. https://doi.org/10.1093/cvr/cvw032
Zhan, Hong ; Aizawa, Kenichi ; Sun, Junqing ; Tomida, Shota ; Otsu, Kinya ; Conway, Simon ; McKinnon, Peter J. ; Manabe, Ichiro ; Komuro, Issei ; Miyagawa, Kiyoshi ; Nagai, Ryozo ; Suzuki, Toru. / Ataxia telangiectasia mutated in cardiac fibroblasts regulates doxorubicin-induced cardiotoxicity. In: Cardiovascular Research. 2016 ; Vol. 110, No. 1. pp. 85-95.
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