Celecoxib impairs heart development via inhibiting cyclooxygenase-2 activity in zebrafish embryos.
BACKGROUND
Celecoxib, a cyclooxygenase-2 inhibitor, is a commonly ingested drug that is used by some women during pregnancy. Although use of celecoxib is associated with increased cardiovascular risk in adults, its effect on fetal heart development remains unknown.


METHODS
Zebrafish embryos were exposed to celecoxib or other relevant drugs from tailbud stage (10.3-72 h postfertilization). Heart looping and valve formation were examined at different developmental stages by in vivo confocal imaging. In addition, whole mount in situ hybridization was performed to examine drug-induced changes in the expression of heart valve marker genes.


RESULTS
In celecoxib-treated zebrafish embryos, the heart failed to undergo normal looping and the heart valve was absent, causing serious blood regurgitation. Furthermore, celecoxib treatment disturbed the restricted expression of the heart valve markers bone morphogenetic protein 4 and versican-but not the cardiac chamber markers cardiac myosin light chain 2, ventricular myosin heavy chain, and atrial myosin heavy chain. These defects in heart development were markedly relieved by treatment with the cyclooxygenase-2 downstream product prostaglandin E2, and mimicked by the cyclooxygenase-2 inhibitor NS398, implying that celecoxib-induced heart defects were caused by the inhibition of cyclooxygenase-2 activity.


CONCLUSIONS
These findings provide the first in vivo evidence that celecoxib exposure impairs heart development in zebrafish embryos by inhibiting cyclooxygenase-2 activity.
Department of Anesthesiology, Xinhua Hospital, Medical School, Shanghai Jiaotong University, Shanghai, China.
Dao-Jie
DJ
Xu
Ji-Wen
JW
Bu
Shan-Ye
SY
Gu
Yi-Meng
YM
Xia
Jiu-Lin
JL
Du
Ying-Wei
YW
Wang
D000082:Acetaminophen / Q000008:administration & dosage; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage; D000704:Analysis of Variance; D000818:Animals; D000068579:Celecoxib; D051546:Cyclooxygenase 2 / Q000187:drug effects*; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000187:drug effects / Q000196:embryology; D006331:Heart Diseases / Q000139:chemically induced* / Q000196:embryology*; D006351:Heart Valves / Q000187:drug effects / Q000196:embryology; D011720:Pyrazoles / Q000008:administration & dosage / Q000009:adverse effects*; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects*; D015027:Zebrafish
D018712:Analgesics, Non-Narcotic; D052246:Cyclooxygenase 2 Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D000082:Acetaminophen; D051546:Cyclooxygenase 2; D000068579:Celecoxib