Dataset Information

Mechanism of action and potential applications of selective inhibition of microsomal prostaglandin E synthase-1-mediated PGE₂ biosynthesis by sonlicromanol's metabolite KH176m.

ABSTRACT: Increased prostaglandin E2 (PGE₂) levels were detected in mitochondrial disease patient cells harboring nuclear gene mutations in structural subunits of complex I, using a metabolomics screening approach. The increased levels of this principal inflammation mediator normalized following exposure of KH176m, an active redox-modulator metabolite of sonlicromanol (KH176). We next demonstrated that KH176m selectively inhibited lipopolysaccharide (LPS) or interleukin-1β (IL-1β)-induced PGE₂ production in control skin fibroblasts. Comparable results were obtained in the mouse macrophage-like cell line RAW264.7. KH176m selectively inhibited mPGES-1 activity, as well as the inflammation-induced expression of mPGES-1. Finally, we showed that the effect of KH176m on mPGES-1 expression is due to the inhibition of a PGE₂-driven positive feedback control-loop of mPGES-1 transcriptional regulation. Based on the results obtained we discuss potential new therapeutic applications of KH176m and its clinical stage parent drug candidate sonlicromanol in mitochondrial disease and beyond.

SUBMITTER: Jiang X

PROVIDER: S-EPMC7806836 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Mechanism of action and potential applications of selective inhibition of microsomal prostaglandin E synthase-1-mediated PGE<sub>2</sub> biosynthesis by sonlicromanol's metabolite KH176m.

Jiang X X Renkema H H Pennings B B Pecheritsyna S S Schoeman J C JC Hankemeier T T Smeitink J J Beyrath J J

Scientific reports 20210113 1

Increased prostaglandin E2 (PGE<sub>2</sub>) levels were detected in mitochondrial disease patient cells harboring nuclear gene mutations in structural subunits of complex I, using a metabolomics screening approach. The increased levels of this principal inflammation mediator normalized following exposure of KH176m, an active redox-modulator metabolite of sonlicromanol (KH176). We next demonstrated that KH176m selectively inhibited lipopolysaccharide (LPS) or interleukin-1β (IL-1β)-induced PGE<s ...[more]

PMID: 33441600

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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.

Dataset Information

Mechanism of action and potential applications of selective inhibition of microsomal prostaglandin E synthase-1-mediated PGE₂ biosynthesis by sonlicromanol's metabolite KH176m.

Publications

Mechanism of action and potential applications of selective inhibition of microsomal prostaglandin E synthase-1-mediated PGE<sub>2</sub> biosynthesis by sonlicromanol's metabolite KH176m.

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Dataset Information

Mechanism of action and potential applications of selective inhibition of microsomal prostaglandin E synthase-1-mediated PGE2 biosynthesis by sonlicromanol's metabolite KH176m.

Publications

Mechanism of action and potential applications of selective inhibition of microsomal prostaglandin E synthase-1-mediated PGE<sub>2</sub> biosynthesis by sonlicromanol's metabolite KH176m.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Mechanism of action and potential applications of selective inhibition of microsomal prostaglandin E synthase-1-mediated PGE₂ biosynthesis by sonlicromanol's metabolite KH176m.