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Title: Ataxia telangiectasia mutated in cardiac fibroblasts regulates doxorubicin-induced cardiotoxicity
Authors: Zhan, H.
Aizawa, K.
Sun, J.
Tomida, S.
Otsu, K.
Conway, S. V.
McKinnon, P.
Manabe, I.
Komuro, I.
Miyagawa, D. K.
Nagai, R.
Suzuki, Toru
First Published: 9-Feb-2016
Publisher: Oxford University Press (OUP)
Citation: Cardiovascular Research (Accepted, In Press)
Abstract: 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.
DOI Link: 10.1093/cvr/cvw032
ISSN: 0008-6363
eISSN: 1755-3245
Embargo on file until: 9-Feb-2017
Version: Post-print
Status: Peer-reviewed
Type: Journal Article
Rights: Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: This is a pre-copyedited, author-produced PDF of an article accepted for publication in Cardiovascular Research following peer review. The version of record Cardiovascular Research (2016) is available online at:
Description: 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.
Appears in Collections:Published Articles, Dept. of Cardiovascular Sciences

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