PubMed · 9345848
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R Botting, J Vane. 1997. Re-addressing relative selectivities.. https://doi.org/10.1016/s0165-6147(97)90654-4
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OBJECTIVE: The purpose of this study was to identify the isoforms and splicing patterns of prostaglandin H synthase present in pregnant human lower-segment myometrium and determine whether there is differential expression of the isoforms or splice variants with respect to gestational age or parturition. STUDY DESIGN: Lower-segment myometrium was collected at cesarean section at term (>37 weeks) or preterm (<37 weeks) from patients who were or were not in labor. Total messenger ribonucleic acid was isolated and reverse transcribed. Polymerase chain reaction for prostaglandin H synthase isoforms 1 and 2 and calponin were performed. Primers designed to characterize the splicing patterns of exon 9 of prostaglandin H synthase-1 were used. RESULTS: The predominant polymerase chain reaction product in all samples corresponds to prostaglandin H synthase-1 messenger ribonucleic acid spliced to include exon 9, but a less-abundant polymerase chain reaction product corresponding to prostaglandin H synthase-1 messenger ribonucleic acid spliced at the internal donor site of exon 9 was also detected. Prostaglandin H synthase-2 messenger ribonucleic acid was detected in human myometrium at a lower abundance than prostaglandin H synthase-1, and neither prostaglandin H synthase-1 or prostaglandin H synthase-2 messenger ribonucleic acid expression changed significantly with gestational age or labor. CONCLUSION: Both prostaglandin H synthase-1 and prostaglandin H synthase-2 isoforms are present in human myometrium. The prostaglandin H synthase-1 messenger ribonucleic acid that includes all of exon 9 encodes the predominant prostaglandin H synthase-1 isoform present in human myometrium. No significant alterations in the expression or splicing patterns for prostaglandin H synthase-1 were detected with respect to gestational age or the onset of labor; but prostaglandin H synthase-1 expression appeared higher at term in anticipation of labor. Although prostaglandin H synthase-2 is present in human myometrium, induction of prostaglandin H synthase-2 does not occur in lower-segment myometrium at parturition.
Endothelial cells possess constitutive or inducible cyclo-oxygenase (COX) isoenzymes for prostacyclin production, but the mechanisms for their expression are largely unknown. We found that vanadate, an inhibitor of protein-tyrosine phosphatases, induced the expression of two COX isoenzyme mRNAs in human umbilical vein endothelial cells (HUVEC) in a time- and dose-dependent manner. Vanadate also stimulated an increase in COX-2 protein levels, but did not affect significantly the levels of constitutively expressed COX-1 protein. Synergistic enhancement of expression of the two COX isoenzyme mRNAs was observed on stimulation of HUVEC with vanadate plus interleukin-1alpha. Tyrphostin-47, which as an inhibitor of protein-tyrosine kinases abolished vanadate-induced protein-tyrosine phosphorylation, inhibited expression of the two COX isoenzyme mRNAs in HUVEC stimulated with vanadate or interleukin-1alpha. These data provide conclusive evidence that activation of protein-tyrosine kinases is causally linked to expression of the mRNAs for the two COX isoenzymes in HUVEC.
Prostaglandin E2, transforming growth factor-beta, and interleukin-1 beta variably regulate the expression of cyclooxygenase 1, cyclooxygenase 2, and lysyl oxidase in IMR90, human embryo lung fibroblasts. Prostaglandin E2 at 100 nM upregulates cyclooxygenase 1 mRNA by approximately three-fold while it downregulates lysyl oxidase mRNA levels. Notably, prostaglandin E2 suppresses the enhancing effect of TGF-beta on basal levels of lysyl oxidase mRNA. These changes in steady state mRNA levels reflect transcriptional level control, at least in part. Corresponding changes are seen in the protein levels of lysyl oxidase, cyclooxygenase 1 and cyclooxygenase 2 and catalytic activities of these enzymes, including net prostaglandin E2 synthesis. Cyclooxygenase 2 mRNA(t1/2, 30 min) is considerably less stable than that of cyclooxygenase 1 (t1/2, 4 h) while lysyl oxidase mRNA is unusually stable (t1/2 > 14 h). Taken together with the differing kinetics with which these genes respond to perturbation by these cytokines, the present results suggest a coordinated, autocrine-like mechanism of regulation of cyclooxygenase 1 and cyclooxygenase 2 and further point to the potential of their metabolic product, prostaglandin E2, to suppress the expression of lysyl oxidase in the inflammatory response to injury.