TY - JOUR
T1 - Disruption of COX-2 modulates gene expression and the cardiac injury response to doxorubicin
AU - Neilan, Tomas G.
AU - Doherty, Glen A.
AU - Chen, Gang
AU - Deflandre, Catherine
AU - McAllister, Hester
AU - Butler, Ryan K.
AU - McClelland, Sarah E.
AU - Kay, Elaine
AU - Ballou, Leslie R.
AU - Fitzgerald, Desmond J.
PY - 2006
Y1 - 2006
N2 - 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 apoptosisinducing 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.
AB - 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 apoptosisinducing 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.
KW - Apoptosis
KW - Cyclooxygenase
UR - http://www.scopus.com/inward/record.url?scp=33746793572&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33746793572&partnerID=8YFLogxK
U2 - 10.1152/ajpheart.00863.2005
DO - 10.1152/ajpheart.00863.2005
M3 - Article
C2 - 16617129
AN - SCOPUS:33746793572
SN - 0363-6135
VL - 291
SP - H532-H536
JO - American Journal of Physiology - Heart and Circulatory Physiology
JF - American Journal of Physiology - Heart and Circulatory Physiology
IS - 2
ER -