Disease relevance of PGHS-2

• Northern blot analysis demonstrated that the messenger RNA (mRNA) abundance of cPLA2 and PGHS-2, but not PGHS-1, increased significantly in the endometrium during both glucocorticoid induced premature labor and spontaneous labor [1].
• This finding indicates that specific PGHS-2 inhibitors are similar to ibuprofen in their ability to compete with aspirin, an irreversible time-dependent inhibitor of PGHS-1 often used for prevention of spontaneous thrombosis [2].
• Previous studies have demonstrated that cerebral ischemia stimulated the increased abundance of immunoreactive PGHS-2, but not PGHS-1, in brain tissue homogenates in late-gestation fetal sheep [3].
• We conclude that cerebral hypoperfusion induced PGHS-2 gene expression in hippocampus, hypothalamus, and brainstem, and we speculate that the increased abundance of the enzyme is likely to be important for control of reflex responses to hypotension in the fetus [3].

High impact information on PGHS-2

• For nimesulide-treated PGHS-2, radical formed in concert with Intermediate II, but later persisted while Intermediate II relaxed [4].
• For PGHS-2, however, the transition between Intermediates I and II was not rate-limiting even at the highest hydroperoxide concentrations tested, indicating that the k2 value for PGHS-2 was much greater than that for PGHS-1 [5].
• Previous work in this laboratory has demonstrated that cerebral hypoperfusion increases the expression of prostaglandin endoperoxide synthase-2 (PGHS-2) in ovine fetal brain regions [6].
• The abundance of both proteins was increased in cerebral cortex in response to BCO, and the abundance of PGHS-2 protein was increased by both oestradiol and BCO in the hippocampus [6].
• One hour after the beginning of a 10 min period of BCO, PGHS-1 mRNA was increased in fetal brainstem and hypothalamus, and PGHS-2 mRNA was increased in fetal brainstem [6].

Chemical compound and disease context of PGHS-2

• Increase in prostaglandin H synthase 2, but not prostaglandin F2alpha synthase mRNA in intrauterine tissues during betamethasone-induced premature labor and spontaneous term labor in sheep [7].
• PGHS2 mRNA increased in endometrium, placenta, and myometrium during betamethasone-induced premature labor and spontaneous term labor [7].

Biological context of PGHS-2

• Progesterone did not have any effect on PGHS-2 gene expression in the myometrium [8].
• Nimesulide reversed the up-regulation of PGHS-2 mRNA that occurred in myometrium, endometrium, and placenta during vehicle infusion (P < 0.05). cPLA2 was only elevated in the endometrium in vehicle infused ewes and did not change in either endometrium or myometrium after nimesulide infusion [9].
• This increase in PGHS-2 mRNA may be required to maintain PGHS-2 enzyme levels during pulsatile secretion of PGF2alpha at luteolysis [10].
• There was an increase in the placental content of PGHS-2 mRNA from around 140 days gestation to term, but no change was found in the level of PGHS-1 mRNA [11].
• We examined whether spontaneous parturition in sheep was associated with tissue-specific changes in prostaglandin H(2) synthase-2 (PGHS-2) expression and/or with altered expression of myometrial EP and FP receptors [12].

Anatomical context of PGHS-2

• Accordingly, we isolated a full-length (3.4 kb) ovine PGHS-2 cDNA from a primary-culture cell model (ovine tracheal epithelial cells) originally described as containing both PGHS isoforms [13].
• In contrast, progesterone was a more potent stimulator than estradiol of PGHS-2 protein abundance in endometrium (P < 0.01) [8].
• PGHS-2 mRNA and protein abundance increased significantly in myometrium after estradiol treatment (P < 0.01) [8].
• In contrast, there were no detectable signals for cPLA2 or PGHS-2 mRNA in either amnion or chorion [1].
• PGHS-2 was immunolocalized in myometrial cells and endometrial glandular epithelial cells, whereas immunoreactive PGHS-1 was located in the myometrial cells, endothelial and smooth muscle cells of blood vessels, as well as epithelial cells of glands and stromal cells in endometrium [8].

Associations of PGHS-2 with chemical compounds

• Thus, there is a rapid increase in endometrial concentrations of PGHS-2 mRNA following oxytocin stimulation of PGF2alpha secretion [10].
• In contrast, progesterone was a more potent stimulator of endometrial PGHS-2 abundance than estradiol [8].
• During nephrogenesis, the insensitivity of PGHS-2, EP(2), and EP(4) expression to down-regulation by cortisol may permit continued PG regulation of renal development and urine formation [14].
• In vitro studies using isolated ovine large luteal cells indicated that mRNA for PGHS-2 was induced by PGF2alpha, phorbol didecanoate, and ionomycin in a pattern similar to that observed in vivo [15].
• Recent evidence suggests that ovine placental output of prostaglandin (PG) E2 rises through late gestation partly because of a direct effect of cortisol on PGH2 synthase 2 (PGHS-2) expression and activity within trophoblast tissue [16].

Other interactions of PGHS-2

• These results are consistent with the hypothesis that the increased expression, of PGFS is responsible for the increased PGF(2 alpha):PGE(2) ratio and this, together with increased PGHS-2 expression, accounts for myometrial activity at labour onset [17].
• METHODS: Chronically catheterized and instrumented fetal sheep were subjected to transient brachiocephalic occlusion (BCO) after intracerebroventricular injection of resveratrol (PGHS-1 or COX-1 inhibitor), nimesulide (PGHS-2 or COX-2 inhibitor), or vehicle [18].
• ER, OTR, Hsp 70 and 90, cPLA2, and PGHS-2 messenger RNA (mRNA) abundance in myometrium, endometrium, and PGHS-2 in placenta were quantified by Northern blot analysis [9].
• Using real-time reverse transcriptase PCR, we have measured the effect of chronic placental restriction (PR) on the renal expression of PG endoperoxide G/H synthase-2 (PGHS-2), PGE(2) receptors EP(2) and EP(4), and renin mRNA in the sheep fetus in late gestation [19].
• Prostaglandin endoperoxide synthase activity in brain tissues decreased with the increased levels of immunoreactive PGHS-2 [20].

Analytical, diagnostic and therapeutic context of PGHS-2

• Molecular cloning, functional expression, and selective regulation of ovine prostaglandin H synthase-2 [13].
• We determined the differential distribution of PGHS-2 and PGHS-1 in ovine myometrium and endometrium with immunocytochemistry [8].
• Expression of PGHS-2 mRNA and protein was determined by in situ hybridization, Western blotting, and immunohistochemistry [12].
• In situ hybridization showed that the distribution of PGHS-2 mRNA was confined to the trophoblasts, with little or no hybridization signal in the maternal endometrium or the maternal syncytium [11].
• Ewes received infusions into the ovarian artery of 1 ml PGF2alpha (1 micromol) or saline, and corpora lutea were collected at various times and analyzed for PGHS-2 mRNA using quantitative, competitive reverse transcription polymerase chain reaction [15].

References