Role of cyclooxygenase isoforms in prostacyclin biosynthesis and murine prehepatic portal hypertension.
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 (PGI(2)), 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 PGI(2) biosynthesis and PHT is not fully understood. Prehepatic PHT was induced by portal vein ligation (PVL) in wild-type, COX-1(-/-), and COX-2(-/-) mice treated with and without COX-2 (NS398) or COX-1 (SC560) inhibitors. Hemodynamic measurements and PGI(2) biosynthesis were determined 1-7 days after PVL or sham surgery. Gene deletion or pharmacological inhibition of COX-1 or COX-2 attenuated but did not ameliorate PGI(2) biosynthesis after PVL or prevent PHT. In contrast, treatment of COX-1(-/-) mice with NS398 or COX-2(-/-) mice with SC560 restricted PGI(2) biosynthesis and abrogated the development of PHT following PVL. In conclusion, either COX-1 or COX-2 can mediate elevated PGI(2) biosynthesis and the development of experimental prehepatic PHT. Consequently, PGI(2) 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 United States alone.
Skill
N J
NJ
Dept. of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA. nskill@iupui.edu
Theodorakis
N G
NG
Wang
Y N
YN
Wu
J M
JM
Redmond
E M
EM
Sitzmann
J V
JV
D000818:Animals; D051545:Cyclooxygenase 1 / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D011464:Epoprostenol / Q000096:biosynthesis* / Q000737:chemistry; D006975:Hypertension, Portal / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D015394:Molecular Structure; D009578:Nitrobenzenes; D020033:Protein Isoforms / Q000378:metabolism; D011720:Pyrazoles; D013449:Sulfonamides
D016861:Cyclooxygenase Inhibitors; D009578:Nitrobenzenes; D020033:Protein Isoforms; D011720:Pyrazoles; C115461:SC 560; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D011464:Epoprostenol; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2
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