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.
Neilan
Tomas G
TG
Department of Clinical Pharmacology, Institute of Biopharmaceutical Sciences, Royal College of Surgeons in Ireland. tneilan@partners.org
Doherty
Glen A
GA
Chen
Gang
G
Deflandre
Catherine
C
McAllister
Hester
H
Butler
Ryan K
RK
McClelland
Sarah E
SE
Kay
Elaine
E
Ballou
Leslie R
LR
Fitzgerald
Desmond J
DJ
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D051546:Cyclooxygenase 2 / Q000235:genetics*; D004317:Doxorubicin / Q000633:toxicity*; D004452:Echocardiography; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D006331:Heart Diseases / Q000139:chemically induced* / Q000201:enzymology* / Q000473:pathology; D006439:Hemodynamics / Q000502:physiology; D016285:Iloprost / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000473:pathology / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014665:Vasodilator Agents / Q000494:pharmacology; D051020:bcl-X Protein / Q000235:genetics
D000970:Antineoplastic Agents; D012333:RNA, Messenger; D014665:Vasodilator Agents; D051020:bcl-X Protein; D004317:Doxorubicin; D051546:Cyclooxygenase 2; C495197:Drak2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D016285:Iloprost