Dataset Information

Inhibition of microsomal PGE synthase-1 reduces human vascular tone by increasing PGI₂ : a safer alternative to COX-2 inhibition.

ABSTRACT:

Background and purpose

The 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 approach

The 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 results

In 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 implications

In 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 articles

This 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.

SUBMITTER: Ozen G

PROVIDER: S-EPMC5660006 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Inhibition of microsomal PGE synthase-1 reduces human vascular tone by increasing PGI<sub>2</sub> : a safer alternative to COX-2 inhibition.

Ozen Gulsev G Gomez Ingrid I Daci Armond A Deschildre Catherine C Boubaya Lilia L Teskin Onder O Uydeş-Doğan B Sonmez BS Jakobsson Per-Johan PJ Longrois Dan D Topal Gokce G Norel Xavier X

British journal of pharmacology 20170811 22

<h4>Background and purpose</h4>The side effects of cyclooxygenase-2 (COX-2) inhibitors on the cardiovascular system could be associated with reduced prostaglandin (PG)I<sub>2</sub> synthesis. Microsomal PGE synthase-1 (mPGES-1) catalyses the formation of PGE<sub>2</sub> from COX-derived PGH<sub>2</sub> . 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 o ...[more]

PMID: 28675448

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Project description:BackgroundTriggering receptor expressed on myeloid cells-1 (TREM-1) is inducible on monocyte/macrophages and neutrophils and amplifies the inflammatory response. The aim of this study was to determine whether rheumatoid arthritis synovial fibroblasts (RASF) promote the expression of TREM-1 in monocytes and its potential regulatory mechanism.MethodsSynovial fluid and paired peripheral blood from rheumatoid arthritis (RA) patients were analyzed using flow cytometry. Expression of TREM-1 in monocytes was detected after co-culture with RASF, with or without pre-treatment with toll-like receptor (TLR) ligands. Whether RASF-regulated TREM-1 level in monocytes require direct cell contact or soluble factors was evaluated by transwell experiment. COX-2 expression and PGE2 secretion in RASF were determined by quantitative PCR (qPCR) and ELISA. RASF, with and without TLR ligand stimulation, were treated with COX-2 inhibitors, COX-2 siRNA (siCOX-2) or EP1-4 antagonists, and the resulting TREM-1 level in CD14+ monocytes was measured using flow cytometry.ResultsTREM-1 was highly expressed in CD14+ cells from peripheral blood and especially synovial fluid from RA patients. The expression of TREM-1 in monocytes was increased by co-culture with RASF. TLR-ligand-activated RASF further elevated TREM-1 level. Transwell assay indicated that soluble factors played a key role in RASF-promoted expression of TREM-1 in monocytes. RASF, with or without stimulation by TLR ligands, increased secretion of PGE2 in a cyclooxygenase (COX)-2-dependent manner. PGE2 enhanced the increase in TREM-1 level in monocytes. Finally, studies using COX-2 inhibitors, COX-2 siRNA (siCOX-2) and EP1-4 antagonists, showed that RASF promotion of TREM-1 expression in monocytes was mediated by COX-2/PGE2/EP2,4 signaling.ConclusionsOur data is the first report to reveal the critical role of RASF in upregulating TREM-1 expression in monocytes, which indicates that TREM-1 might be a novel target for RA therapy.

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.

Dataset Information

Inhibition of microsomal PGE synthase-1 reduces human vascular tone by increasing PGI₂ : a safer alternative to COX-2 inhibition.

Background and purpose

Experimental approach

Key results

Conclusions and implications

Linked articles

Publications

Inhibition of microsomal PGE synthase-1 reduces human vascular tone by increasing PGI<sub>2</sub> : a safer alternative to COX-2 inhibition.

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Dataset Information

Inhibition of microsomal PGE synthase-1 reduces human vascular tone by increasing PGI2 : a safer alternative to COX-2 inhibition.

Background and purpose

Experimental approach

Key results

Conclusions and implications

Linked articles

Publications

Inhibition of microsomal PGE synthase-1 reduces human vascular tone by increasing PGI<sub>2</sub> : a safer alternative to COX-2 inhibition.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Inhibition of microsomal PGE synthase-1 reduces human vascular tone by increasing PGI₂ : a safer alternative to COX-2 inhibition.