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

BACKGROUND AND PURPOSE The side effects of cyclooxygenase-2 (COX-2) inhibitors on the cardiovascular system could be associated with reduced prostaglandin (PG)I-2 synthesis. Microsomal PGE synthase-1 (mPGES-1) catalyses the formation of PGE(2) from COX-derived PGH(2). 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 internalmammary 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 PGE(2) and PGI(2) 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 (PGI(2) receptor) antagonist but not modified by NOS inhibition. Moreover, PGI(2) release was increased with the mPGES-1 inhibitor and decreased with the COX-2 inhibitor, while both inhibitors reduced PGE(2) release. CONCLUSIONS AND IMPLICATIONS In contrast to COX-2 inhibition, inhibition ofmPGES-1 reduced vasoconstriction by increasing PGI(2) synthesis. Targetingm-PGES-1 could provide a lower risk of cardiovascular side effects, compared with those of the COX-2 inhibitors.