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Biological characterization of new inhibitors of microsomal PGE synthase-1 in preclinical models of inflammation and vascular tone.

ABSTRACT: BACKGROUND AND PURPOSE:Microsomal PGE synthase-1 (mPGES-1), the inducible synthase that catalyses the terminal step in PGE₂ biosynthesis, is of high interest as therapeutic target to treat inflammation. Inhibition of mPGES-1 is suggested to be safer than traditional NSAIDs, and recent data demonstrate anti-constrictive effects on vascular tone, indicating new therapeutic opportunities. However, there is a lack of potent mPGES-1 inhibitors lacking interspecies differences for conducting in vivo studies in relevant preclinical disease models. EXPERIMENTAL APPROACH:Potency was determined based on the reduction of PGE₂ formation in recombinant enzyme assays, cellular assay, human whole blood assay, and air pouch mouse model. Anti-inflammatory properties were assessed by acute paw swelling in a paw oedema rat model. Effect on vascular tone was determined with human ex vivo wire myography. KEY RESULTS:We report five new mPGES-1 inhibitors (named 934, 117, 118, 322, and 323) that selectively inhibit recombinant human and rat mPGES-1 with IC₅₀ values of 10-29 and 67-250 nM respectively. The compounds inhibited PGE₂ production in a cellular assay (IC₅₀ values 0.15-0.82 ?M) and in a human whole blood assay (IC₅₀ values 3.3-8.7 ?M). Moreover, the compounds blocked PGE₂ formation in an air pouch mouse model and reduced acute paw swelling in a paw oedema rat model. Human ex vivo wire myography analysis showed reduced adrenergic vasoconstriction after incubation with the compounds. CONCLUSION AND IMPLICATIONS:These mPGES-1 inhibitors can be used as refined tools in further investigations of the role of mPGES-1 in inflammation and microvascular disease.

SUBMITTER: Larsson K

PROVIDER: S-EPMC6965680 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Biological characterization of new inhibitors of microsomal PGE synthase-1 in preclinical models of inflammation and vascular tone.

Larsson Karin K Steinmetz Julia J Bergqvist Filip F Arefin Samsul S Spahiu Linda L Wannberg Johan J Pawelzik Sven-Christian SC Morgenstern Ralf R Stenberg Patric P Kublickiene Karolina K Korotkova Marina M Jakobsson Per-Johan PJ

British journal of pharmacology 20191228 24

<h4>Background and purpose</h4>Microsomal PGE synthase-1 (mPGES-1), the inducible synthase that catalyses the terminal step in PGE<sub>2</sub> biosynthesis, is of high interest as therapeutic target to treat inflammation. Inhibition of mPGES-1 is suggested to be safer than traditional NSAIDs, and recent data demonstrate anti-constrictive effects on vascular tone, indicating new therapeutic opportunities. However, there is a lack of potent mPGES-1 inhibitors lacking interspecies differences for c ...[more]

PMID: 31404942

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Project description:Background and purposeThe side effects of cyclooxygenase-2 (COX-2) inhibitors on the cardiovascular system could be associated with reduced prostaglandin (PG)I2 synthesis. Microsomal PGE synthase-1 (mPGES-1) catalyses the formation of PGE2 from COX-derived PGH2 . This enzyme is induced under inflammatory conditions and constitutes an attractive target for novel anti-inflammatory drugs. However, it is not known whether mPGES-1 inhibitors could be devoid of cardiovascular side effects. The aim of this study was to compare, in vitro, the effects of mPGES-1 and COX-2 inhibitors on vascular tone in human blood vessels.Experimental approachThe vascular tone and prostanoid release from internal mammary artery (IMA) and saphenous vein (SV) incubated for 30 min with inhibitors of mPGES-1 or COX-2 were investigated under normal and inflammatory conditions.Key resultsIn inflammatory conditions, mPGES-1 and COX-2 proteins were more expressed, and increased levels of PGE2 and PGI2 were released. COX-2 and NOS inhibitors increased noradrenaline induced vascular contractions in IMA under inflammatory conditions while no effect was observed in SV. Interestingly, the mPGES-1 inhibitor significantly reduced (30-40%) noradrenaline-induced contractions in both vessels. This effect was reversed by an IP (PGI2 receptor) antagonist but not modified by NOS inhibition. Moreover, PGI2 release was increased with the mPGES-1 inhibitor and decreased with the COX-2 inhibitor, while both inhibitors reduced PGE2 release.Conclusions and implicationsIn contrast to COX-2 inhibition, inhibition of mPGES-1 reduced vasoconstriction by increasing PGI2 synthesis. Targeting mPGES-1 could provide a lower risk of cardiovascular side effects, compared with those of the COX-2 inhibitors.Linked articlesThis article is part of a themed section on Targeting Inflammation to Reduce Cardiovascular Disease Risk. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.22/issuetoc and http://onlinelibrary.wiley.com/doi/10.1111/bcp.v82.4/issuetoc.

Project description:We recently reported that aldo-keto reductase 1B3-produced prostaglandin (PG) F(2?) suppressed the early phase of adipogenesis. PGE(2) is also known to suppress adipogenesis. In this study, we found that microsomal PGE(2) synthase (PGES)-1 (mPGES-1; PTGES1) acted as the PGES in adipocytes and that PGE(2) and PGF(2?) synergistically suppressed the early phase of adipogenesis. PGE(2) production was detected in preadipocytes and transiently enhanced at 3 h after the initiation of adipogenesis of mouse adipocytic 3T3-L1 cells, followed by a quick decrease; and its production profile was similar to the expression of the cyclooxygenase-2 (PTGS2) gene. When 3T3-L1 cells were transfected with siRNAs for any one of the three major PTGESs, i.e., PTGES1, PTGES2 (mPGES-2), and PTGES3 (cytosolic PGES), only PTGES1 siRNA suppressed PGE(2) production and enhanced the expression of adipogenic genes. AE1-329, a PTGER4 (EP4) receptor agonist, increased the expression of the Ptgs2 gene with a peak at 1 h after the initiation of adipogenesis. PGE(2)-mediated enhancement of the PTGS2 expression was suppressed by the co-treatment with L-161982, a PTGER4 receptor antagonist. Moreover, AE1-329 enhanced the expression of the Ptgs2 gene by binding of the cyclic AMP response element (CRE)-binding protein to the CRE of the Ptgs2 promoter; and its binding was suppressed by co-treatment with L-161982, which was demonstrated by promoter luciferase and chromatin immunoprecipitation assays. Furthermore, when 3T3-L1 cells were caused to differentiate into adipocytes in medium containing both PGE(2) and PGF(2?), the expression of the adipogenic genes and the intracellular triglyceride level were decreased to a greater extent than in medium containing either of them, revealing that PGE(2) and PGF(2?) independently suppressed adipogenesis. These results indicate that PGE(2) was synthesized by PTGES1 in adipocytes and synergistically suppressed the early phase of adipogenesis of 3T3-L1 cells in cooperation with PGF(2?) through receptor-mediated activation of PTGS2 expression.

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Biological characterization of new inhibitors of microsomal PGE synthase-1 in preclinical models of inflammation and vascular tone.

Publications

Biological characterization of new inhibitors of microsomal PGE synthase-1 in preclinical models of inflammation and vascular tone.

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