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Prostaglandin G/H Synthase (PGHS)-2 Expression in Bovine Myometrium: Influence of Steroid Hormones and PGHS Inhibitors¹

^a Perinatal Research and Developmental Pharmacology Unit, Lady Davis Institute for Medical Research, McGill University, Montréal, Québec, Canada H3T 1E2 ^b Unité de Génétique, Pavillon Saint-François d'Assise, ^c Laboratoire de Rhumatologie et Immunologie, ^d Unité de Recherche en Ontogénie et Reproduction, Pavillon C.H.U.L., Laval University, Québec, Canada G1V 4G2

Prostaglandins (PGs) are important mediators regulating uterine functions during the reproductive process. The objective of this study was to examine, in myocytes from the circular and longitudinal layers of bovine myometrium, the relative levels of mRNA and proteins corresponding to the gene expression of key enzymes (phospholipase A₂; prostaglandin G/H synthase-1 [PGHS-1]; prostaglandin G/H synthase-2 [PGHS-2]; prostaglandin I₂ synthase) involved in PG biosynthesis.

We examined the influence of estradiol-17ß and progesterone on the expression and activity of these enzymes. Treatment of myocytes with progesterone (P₄: 10 nM, 24 h) in the absence or presence of estradiol-17ß (E₂: 1 nM, 72 h) suppressed PG biosynthesis by approximately 60% in both myometrial layers. No significant effect was observed after E₂ treatment. The combined effect of E₂ and P₄ on PG accumulation was correlated with the modulation of PGHS-2 protein and mRNA levels in the two myometrial layers without affecting other enzymes of the PG cascade. Selective or nonselective inhibition of PGHS activity with CGP 28238 (PGHS-2-specific; a product from Ciba-Geigy: 6-[2,4-difluorophenoxy]-5-methyl-sulfonylamino-1-indanone) or indomethacin (PGHS-1 and -2) reduced prostacyclin accumulation (measured as 6-keto-PGF₁ in the culture medium) in a dose-dependent manner in the two myometrial layers. A significant inhibitory effect was obtained at a low concentration of indomethacin (1 nM, p < 0.05) compared to CGP 28238 (10 nM, p < 0.05). In both myometrial layers, the maximal effect of indomethacin and/or CGP 28238 on PG accumulation was observed at 100 nM and represented 85% and 65% inhibition, respectively. In the presence of phorbol 12-myristate (100 nM), CGP 28238 (10 nM) significantly suppressed PGHS-2 mRNA level by 44.80 ± 7.67% (p < 0.01) and 27.83 ± 7.62% (p < 0.05) in the longitudinal and circular layer, respectively. In contrast, indomethacin did not have any significant effect. These data constitute the first quantitative analysis of key enzymes involved in PG biosynthesis in separated myometrial layers. Furthermore, the results provide interesting information on the CGP 28238 drug modulating both enzymatic activity and mRNA expression of PGHS-2.

¹ This work was supported in part by grants #OGP0183695 (F.D-B.) and #OGPIN030 (M.A.F.) from the Natural Sciences and Engineering Research Council of Canada (NSERC).

² Correspondence: Florence Doualla-Bell, Perinatal Research and Developmental, Pharmacology Unit, Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 chemin de la Côte-Ste-Catherine, Montréal, PQ, Canada H3T 1E2. FAX: 514 340 7573; fdoualla{at}ldi.jgh.mcgill.ca

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