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This Article Full Text Full Text (PDF) All Versions of this Article: 291/2/H532    most recent 00863.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Neilan, T. G. Articles by Fitzgerald, D. J. Search for Related Content PubMed PubMed Citation Articles by Neilan, T. G. Articles by Fitzgerald, D. J.

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Regulation of Cardiovascular Functions by Eicosanoids and other Lipid Mediators

Disruption of COX-2 modulates gene expression and the cardiac injury response to doxorubicin

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

Submitted 12 August 2005 ; accepted in final form 13 January 2006

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 compared with 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^–/– mice 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^–/– mice was attenuated by a prostacyclin analog, suggesting a protective role for prostaglandins in this setting.

apoptosis; cyclooxygenase

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