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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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