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

Br J Pharmacol. 2017 Nov;174(22):4087-4098. doi: 10.1111/bph.13939. Epub 2017 Aug 11.

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.

MeSH terms

  • Aged
  • Cyclooxygenase 2 / metabolism
  • Cyclooxygenase 2 / physiology
  • Cyclooxygenase Inhibitors / pharmacology
  • Epoprostenol / metabolism
  • Epoprostenol / physiology*
  • Female
  • Humans
  • Inflammation / metabolism
  • Inflammation / physiopathology
  • Male
  • Mammary Arteries / drug effects
  • Mammary Arteries / metabolism
  • Mammary Arteries / physiology*
  • Middle Aged
  • Norepinephrine / pharmacology
  • Prostaglandin-E Synthases / antagonists & inhibitors
  • Prostaglandin-E Synthases / metabolism
  • Prostaglandin-E Synthases / physiology*
  • Saphenous Vein / drug effects
  • Saphenous Vein / metabolism
  • Saphenous Vein / physiology*
  • Thiophenes / pharmacology
  • Vasoconstrictor Agents / pharmacology

Substances

  • Cyclooxygenase Inhibitors
  • Thiophenes
  • Vasoconstrictor Agents
  • DuP 697
  • Epoprostenol
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • PTGES protein, human
  • Prostaglandin-E Synthases
  • Norepinephrine