Role of cyclooxygenase isoforms in prostacyclin biosynthesis and murine prehepatic portal hypertension

N. Skill, N. G. Theodorakis, Y. N. Wang, J. M. Wu, E. M. Redmond, J. V. Sitzmann

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

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. 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 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. In conclusion, either COX-1 or COX-2 can mediate elevated PGI2 biosynthesis and the development of experimental prehepatic 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 United States alone.

Original languageEnglish
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume295
Issue number5
DOIs
StatePublished - Nov 2008

Fingerprint

Portal Hypertension
Epoprostenol
Prostaglandin-Endoperoxide Synthases
Protein Isoforms
Cyclooxygenase 1
Portal Vein
Ligation
Cyclooxygenase 2
Gene Deletion
Non-Steroidal Anti-Inflammatory Agents
Liver Cirrhosis
Fibrosis
Hemodynamics
Pharmacology
Morbidity
Mortality
Therapeutics

Keywords

  • Gene-deficient mice
  • Portal vein ligation

ASJC Scopus subject areas

  • Gastroenterology
  • Physiology (medical)
  • Physiology
  • Hepatology

Cite this

Role of cyclooxygenase isoforms in prostacyclin biosynthesis and murine prehepatic portal hypertension. / Skill, N.; Theodorakis, N. G.; Wang, Y. N.; Wu, J. M.; Redmond, E. M.; Sitzmann, J. V.

In: American Journal of Physiology - Gastrointestinal and Liver Physiology, Vol. 295, No. 5, 11.2008.

Research output: Contribution to journalArticle

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