Submitted on January 9, 2008
Accepted on August 20, 2008
Role of cyclooxygenase isoforms in prostacyclin biosynthesis and murine pre-hepatic portal hypertension
Nicholas James Skill1*, Nicholas G Theodorakis1, Yinning N Wang2, Jian-Min Wu3, Eileen M Redmond2, and James V Sitzmann4
1 Surgery, Indiana University, Indianpolis, United States
2 Surgery, University of Rochester, Rochester, New York, United States
3 Surgery, Indiana University, Indianapolis, Indiana, United States
4 Surgery, Indiana University, Indianpolis, United States; Physiology and Pharacology, Indiana University, Indianapolis, United States
* To whom correspondence should be addressed. E-mail: nskill{at}iupui.edu.
Portal hypertension (PHT) is a common complication of liver cirrhosis and significantly increases morbidity and mortality. Abrogation of PHT using NSAIDs has demonstrated that prostacyclin (PGI2), a direct downstream metabolic product of cyclooxygenase (COX) activity, is an important mediator in the development of experimental and clinical PHT. However, the role of COX isoforms in PGI2 biosynthesis and PHT is not fully understood. Methods: Pre-hepatic PHT was induced by portal vein ligation (PVL) in wild-type, COX-1-/- and COX-2-/- mice treated with/without COX-2 (NS398) or COX-1 (SC560) inhibitors. Hemodynamic measurements and PGI2 biosynthesis were determined 1-7d after PVL or sham surgery. Results: Gene deletion, or pharmacological inhibition of COX-1 or COX-2 attenuated but did not ameliorate PGI2 biosynthesis after PVL or prevent PHT. In contrast, treatment of COX-1-/- mice with NS398 or COX-2-/- mice with SC560 restricted PGI2 biosynthesis and abrogated the development of PHT following PVL. Conclusion: Either COX-1 or COX-2 can mediate elevated PGI2 biosynthesis and the development of experimental pre-hepatic PHT. Consequently, PGI2 rather then COX selective drugs are indicated in the treatment of PHT. Identification of additional target sites downstream of COX may benefit the >27,000 patients whom die annually from cirrhosis in the US alone.
