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Am J Physiol Heart Circ Physiol (April 14, 2006). doi:10.1152/ajpheart.00863.2005
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Submitted on August 12, 2005
Accepted on January 13, 2006

Disruption of COX-2 Modulates Gene Expression and the Cardiac Injury Response to Doxorubicin

Tomas G Neilan1*, Glen A Doherty1, Gang Chen2, Catherine Deflandre3, Hester McAllister3, Ryan K Butler1, Sarah E McClelland1, Elaine Kay4, Leslie R Ballou5, and Desmond J Fitzgerald1

1 Department of Clinical Pharmacology, Institute of Biopharmaceutical Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
2 Department of Surgery, Beaumont Hospital, Ireland
3 Department of Veterinary Medicine, University College Dublin, Dublin, Ireland
4 Department of Pathology, Beaumont Hospital, Dublin, Ireland
5 Department of Veterans Affairs Medical Centre, Departments of Medicine and Molecular Sciences, University of Tennessee, Memphis, United States

* To whom correspondence should be addressed. E-mail: tneilan{at}partners.org.

To determine the role of cyclooxygenase (COX)-2 in anthracycline-induced cardiac toxicity, we administered doxorubicin (DOX) to mice with genetic disruption of COX-2 (COX-2-/-). After treatment with DOX, COX-2-/- mice had increased cardiac dysfunction and cardiac cell apoptosis as compared to DOX-treated wild-type mice. The expression of the death-associated protein kinase-related apoptosis-inducing protein kinase-2 was also increased in DOX-treated COX-2-/- animals. The altered gene expression, cardiac injury and dysfunction after DOX treatment in COX-2-/- was attenuated by a stable prostacyclin analog, iloprost. Wild-type mice treated with DOX developed cardiac fibrosis that was absent in COX-2-/- mice and unaffected by iloprost. These results suggest that genetic disruption of COX-2 increases the cardiac dysfunction after treatment with DOX by an increase in cardiac cell apoptosis. This DOX-induced cardiotoxicity in COX-2-/- was attenuated by a prostacyclin analog, suggesting a protective role for prostaglandins in this setting.




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