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Ataxia telangiectasia mutated in cardiac fibroblasts regulates doxorubicin-induced cardiotoxicity

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journal contribution
posted on 2016-02-22, 10:54 authored by H. Zhan, K. Aizawa, J. Sun, S. Tomida, K. Otsu, S. V. Conway, P. McKinnon, I. Manabe, I. Komuro, D. K. Miyagawa, R. Nagai, Toru Suzuki
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.

History

Citation

Cardiovascular Research (Accepted, In Press)

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicine/Department of Cardiovascular Sciences

Version

  • AM (Accepted Manuscript)

Published in

Cardiovascular Research (Accepted

Publisher

Oxford University Press (OUP)

issn

0008-6363

eissn

1755-3245

Acceptance date

2016-02-09

Copyright date

2016

Available date

2017-02-09

Publisher version

http://cardiovascres.oxfordjournals.org/content/early/2016/02/09/cvr.cvw032

Notes

The file associated with this record is under a 12-month embargo from publication in accordance with the publisher's self-archiving policy. The full text may be available through the publisher links provided above.

Language

en

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