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

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.