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|Title:||Ataxia telangiectasia mutated in cardiac fibroblasts regulates doxorubicin-induced cardiotoxicity|
Conway, S. V.
Miyagawa, D. K.
|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.|
|Embargo on file until:||9-Feb-2017|
|Rights:||Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: firstname.lastname@example.org. 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: dx.doi.org/10.1093/cvr/cvw032|
|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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|cvr.cvw032.full.pdf||Post-review (final submitted)||1.64 MB||Adobe PDF||View/Open|
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