Selective inhibition of prostacyclin synthase activity by rofecoxib

Cristiana Griffoni, Enzo Spisni, Antonio Strillacci, Mattia Toni, Markus Michael Bachschmid, Vittorio Tomasi

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

The development of cyclooxygenase-2 (COX-2) selective inhibitors prompted studies aimed at treating chronic inflammatory diseases and cancer by using this new generation of drugs.Yet, several recent reports pointed out that long-term treatment of patients with COX-2 selective inhibitors (especially rofecoxib) caused severe cardiovascular complicances. The aim of this study was to ascertain whether, in addition to inhibiting COX-2, rofecoxib may also affect prostacyclin (PGI2) level by inhibiting PGI2 forming enzyme (prostacyclin synthase, PGIS). In order to evaluate if selective (celecoxib, rofecoxib) and non-selective (aspirin, naproxen) anti-inflammatory compounds could decrease PGI2 production in endothelial cells by inhibiting PGIS, we analyzed the effect of anti-inflammatory compounds on the enzyme activity by ELISA assay after addition of exogenous substrate, on PGIS protein levels by Western blotting and on its subcellular distribution by confocal microscopy. We also analyzed the effect of rofecoxib on PGIS activity in bovine aortic microsomal fractions enriched in PGIS. This study demonstrates an inhibitory effect of rofecoxib on PGIS activity in human umbilical vein endothelial (HUVE) cells and in PGIS-enriched bovine aortic microsomal fractions, which is not observed by using other anti-inflammatory compounds. The inhibitory effect of rofecoxib is associated neither to a decrease of PGIS protein levels nor to an impairment of the enzyme intracellular localization. The results of this study may explain the absence of a clear relationship between COX-2 selectivity and cardiovascular side effects. Moreover, in the light of these results we propose that novel selective COX-2 inhibitors should be tested on PGI2 synthase activity inhibition.

Original languageEnglish
Pages (from-to)327-338
Number of pages12
JournalJournal of Cellular and Molecular Medicine
Volume11
Issue number2
DOIs
Publication statusPublished - Mar 2007

Fingerprint

Epoprostenol
Cyclooxygenase 2
Cyclooxygenase 2 Inhibitors
Anti-Inflammatory Agents
Celecoxib
Endothelial cells
Enzymes
Naproxen
Confocal microscopy
Human Umbilical Vein Endothelial Cells
Enzyme activity
Confocal Microscopy
Aspirin
rofecoxib
prostacyclin synthetase
Assays
Proteins
Chronic Disease
Endothelial Cells
Western Blotting

Keywords

  • Cyclooxygenase-2 inhibitors
  • Endothelium
  • Nonsteroidal anti-inflammatory agents
  • Prostacyclin synthase
  • Rofecoxib

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry

Cite this

Griffoni, C., Spisni, E., Strillacci, A., Toni, M., Bachschmid, M. M., & Tomasi, V. (2007). Selective inhibition of prostacyclin synthase activity by rofecoxib. Journal of Cellular and Molecular Medicine, 11(2), 327-338. https://doi.org/10.1111/j.1582-4934.2007.00021.x

Selective inhibition of prostacyclin synthase activity by rofecoxib. / Griffoni, Cristiana; Spisni, Enzo; Strillacci, Antonio; Toni, Mattia; Bachschmid, Markus Michael; Tomasi, Vittorio.

In: Journal of Cellular and Molecular Medicine, Vol. 11, No. 2, 03.2007, p. 327-338.

Research output: Contribution to journalArticle

Griffoni, C, Spisni, E, Strillacci, A, Toni, M, Bachschmid, MM & Tomasi, V 2007, 'Selective inhibition of prostacyclin synthase activity by rofecoxib', Journal of Cellular and Molecular Medicine, vol. 11, no. 2, pp. 327-338. https://doi.org/10.1111/j.1582-4934.2007.00021.x
Griffoni, Cristiana ; Spisni, Enzo ; Strillacci, Antonio ; Toni, Mattia ; Bachschmid, Markus Michael ; Tomasi, Vittorio. / Selective inhibition of prostacyclin synthase activity by rofecoxib. In: Journal of Cellular and Molecular Medicine. 2007 ; Vol. 11, No. 2. pp. 327-338.
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