Abstract
Patent ductus arteriosus (DA) is the second most common congenital heart defect, the incidence of which is increased in premature infants, although mechanisms responsible are not clear. Our previous studies with genetic or pharmacological inactivation of cyclooxygenase-2 (COX-2) in mice, emphasized the importance of this enzyme in normal DA closure. The current study was designed to determine whether reduced COX-2 expression contributes to patent DA in preterm mice. Real-time PCR analysis indicated that COX-2 expression in the fetal mouse DA significantly increased with advancing gestational age. Furthermore, we observed a significant induction in COX-2 expression in the DA at 3 h after birth at full-term gestation. In contrast, COX-2 expression was significantly attenuated in the DA of preterm neonatal mice. DA closure was incomplete in preterm mice at 3 h postpartum, a time-point when the DA of full-term neonates was completely remodeled. Additionally, COX-2 expression was significantly attenuated in the DA of mice deficient in the prostanoid receptor EP4, which also show a patent DA phenotype, suggesting the importance of this receptor for the induction of COX-2 required for DA closure. Overall, these studies suggest that attenuated expression of COX-2 may contribute to increased patent DA at preterm gestation.
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Abbreviations
- DA:
-
ductus arteriosus
- COX:
-
cyclooxygenase
- E:
-
eosin
- H:
-
hematoxylin
- HPRT:
-
hypoxanthine phospho-ribosyl transferase
- PG:
-
prostaglandin
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Acknowledgements
The authors thank Dr. Robert Langenbach (National Institutes of Health/National Institute of Environmental Health Sciences, Research Triangle Park, NC) for providing the breeder pairs of COX-2 wild-type mice and Drs. Shuh Narumiya (Kyoto University, Kyoto, Japan) and Takayuki Maruyama (Ono Pharmaceuticals, Osaka, Japan) for the EP4 heterozygous-deficient breeding pairs.
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This work was supported by a Scientist Development Grant (0430153N) from the American Heart Association.
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Trivedi, D., Sugimoto, Y. & Loftin, C. Attenuated Cyclooxygenase-2 Expression Contributes to Patent Ductus Arteriosus in Preterm Mice. Pediatr Res 60, 669–674 (2006). https://doi.org/10.1203/01.pdr.0000246480.13170.c0
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DOI: https://doi.org/10.1203/01.pdr.0000246480.13170.c0
