Regulation of Prostaglandin Synthesis in Human Vascular Cells (original) (raw)
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Prostaglandin and thromboxane biosynthesis
Pharmacology & Therapeutics, 1991
We describe the enzymological regulation of the formation of prostaglandin (PG) D 2, PGE2, PGF2,, 9~,1 Ifl-PGF2, PGI2 (prostacyclin), and thromboxane (Tx) A 2 from arachidonic acid. We discuss the three major steps in prostanoid formation: (a) arachidonate mobilization from monophosphatidylinositol involving phospholipase C, diglyceride lipase, and monoglyceride lipase and from phosphatidylcholine involving phospholipase A2; (b) formation of prostaglandin endoperoxides (PGG 2 and PGHz) catalyzed by the cyclooxygenase and peroxidase activities of PGH synthase; and (c) synthesis of PGD 2, PGE2, PGF~, 9a, l 1/~-PGF2, PGI2, and TxA 2 from PGH 2. We also include information on the roles of aspirin and other nonsteroidal anti-inflammatory drugs, dexamethasone and other anti-inflammatory steroids, platelet-derived growth factor (PDGF), and interleukin-1 in prostaglandin metabolism. CONTENTS 159 3.9. Glucocorticoids and phospholipase inhibition 159 4. Prostaglandin Endoperoxide Formation 160 4.1. PGH synthase catalysis-an overview 160 4.2. Cyclooxygenase catalysis 160 4.3. Cyclooxygenase inhibition-nonsteroidal anti-inflammatory drugs 161 4.4. Peroxidase catalysis 161 4.5. Peroxidase-dependent cooxidation of reducing cosubstrates 162 4.6. Interdependence of cyclooxygenase and peroxidase reactions 162 4.7. Suicide reactions 163 4.8. Physico-chemical properties of PGH synthase 163 4.9. PGH synthase amino acid sequence 163 4.10. Heme binding site 164 4.11. Active site model of PGH synthase 165 4.12. Regulation of PGH synthase protein concentrations 165 4.13. Developmental regulation of PGH synthase 167 4.14. 'Tuning' of PGH synthase 167 4.15. Intracellular regulation of PGH synthase 167 4.16. Pools of PGH synthase 168 4.17. PGH synthase gene structure 168 4.18. Effects of anti-inflammatory steroids on PGH synthase
PLoS ONE, 2013
This study aimed at evaluating the relative contribution of endothelial cyclooxygenase-1 and-2 (COX-1 and COX-2) to prostacyclin (PGI 2) production in the presence of mild oxidative stress resulting from autooxidation of polyphenols such as (-)-epigallocatechin 3-gallate (EGCG), using both endothelial cells in culture and isolated blood vessels. EGCG treatment resulted in an increase in hydrogen peroxide formation in human umbilical vein endothelial cells. In the presence of exogenous arachidonic acid and EGCG, PGI 2 production was preferentially inhibited by a selective COX-1 inhibitor. This effect of selective inhibition was also substantially reversed by catalase. In addition, EGCG caused vasorelaxation of rat aortic ring only partially abolished by a nitric oxide synthase inhibitor. Concomitant treatment with a selective COX-1 inhibitor completely prevented the vasorelaxation as well as the increase in PGI 2 accumulation in the perfusate observed in EGCGtreated aortic rings, while a selective COX-2 inhibitor was completely uneffective. Our data strongly support the notions that H 2 O 2 generation affects endothelial PGI 2 production, making COX-1, and not COX-2, the main source of endothelial PGI 2 under altered oxidative tone conditions. These results might be relevant to the reappraisal of the impact of COX inhibitors on vascular PGI 2 production in patients undergoing significant oxidative stress.
Journal of Biological Chemistry, 1999
The two cyclooxygenase isoforms, cyclooxygenase-1 and cyclooxygenase-2, both metabolize arachidonic acid to prostaglandin H2, which is subsequently processed by downstream enzymes to the various prostanoids. In the present study, we asked if the two isoforms differ in the profile of prostanoids that ultimately arise from their action on arachidonic acid. Resident peritoneal macrophages contained only cyclooxygenase-1 and synthesized (from either endogenous or exogenous arachidonic acid) a balance of four major prostanoids: prostacyclin, thromboxane A2, prostaglandin D2, and 12-hydroxyheptadecatrienoic acid. Prostaglandin E2 was a minor fifth product, although these cells efficiently converted exogenous prostaglandin H2 to prostaglandin E2. By contrast, induction of cyclooxygenase-2 with lipopol- ysaccharide resulted in the preferential production of prostacyclin and prostaglandin E2. This shift in product profile was accentuated if cyclooxygenase-1 was permanently inactivated with aspirin before cyclooxygenase-2 induction. The conversion of exogenous prostaglandin H2 to prostaglandin E2 was only modestly increased by lipopolysaccharide treatment. Thus, cyclooxygenase-2 induction leads to a shift in arachidonic acid metabolism from the production of several prostanoids with diverse effects as mediated by cyclooxygenase-1 to the preferential synthesis of two prostanoids, prostacyclin and prostaglandin E2, which evoke common effects at the cellular level.
Prostaglandin Endoperoxides. Novel Transformations of Arachidonic Acid in Human Platelets
Proceedings of the National Academy of Sciences, 1974
Arachidonic acid incubated with human platelets was converted into three compounds, 12L-hydroxy-5,8,10,14-eicosatetraenoic acid, 12L-hydroxy-5,8,10-heptadecatrienoic acid, and the hemiacetal derivative of 8-(1-hydroxy-3-oxopropyl)-9,12L-dihydroxy-5,10-heptadecadienoic acid. The formation of the two latter compounds from arachidonic acid proceeded by pathways involving the enzyme, fatty acid cyclo-oxygenase, in the initial step and with the prostaglandin endoperoxide, PGG(2), as an intermediate. The first mentioned compound was formed from 12L-hydroperoxy-5,8,10,14-eicosatetraenoic acid, which in turn was formed from arachidonic acid by the action of a novel lipoxygenase. Aspirin and indomethacin inhibited the fatty acid cyclo-oxygenase but not the lipoxygenase, whereas 5,8,11,14-eicosatetraynoic acid inhibited both enzymes. The almost exclusive transformation of the endoperoxide structure into non-prostaglandin derivatives supports the hypothesis that the endoperoxides can participate directly and not by way of the classical prostaglandins in regulation of cell functions. The observed transformations of arachidonic acid in platelets also explain the aggregating effect of this acid.