Balance Between PGD Synthase and PGE Synthase Is a Major Determinant of Atherosclerotic Plaque Instability in Humans

Abstract

Objective— Inducible cyclooxygenase (COX-2) catalyzes the first step in prostanoid biosynthesis and is considered a proinflammatory enzyme. COX-2 and type 1 inducible PGE synthase (mPGES-1) have a role in metalloproteinase (MMP) release leading to plaque rupture. In contrast, lipocalin-type PGD synthase (L-PGDS) has been shown to exert antiinflammatory actions. Thus, in this study we investigated whether a shift from a PGDS-oriented to a PGES-oriented profile in arachidonate metabolism leads to inflammatory activation in rupture-prone plaque macrophages. Methods and Results— Atherosclerotic plaques were obtained from 60 patients who underwent carotid endarterectomy, symptomatic (n=30) and asymptomatic (n=30) according to evidence of recent transient ischemic attack or stroke. Plaques were analyzed for COX-2, mPGES-1, L-PGDS, PPARγ, IκBα, NF-κB, and MMP-9 by immunocytochemistry, Western blot, reverse-transcriptase polymerase chain reaction, enzyme immunoassay, and zymography. Prostaglandin E ₂ (PGE ₂ ) pathway was significantly prevalent in symptomatic plaques, whereas PGD ₂ pathway was overexpressed in asymptomatic ones, associated with NF-κB inactivation and MMP-9 suppression. In vitro COX-2 inhibition in monocytes was associated with reduced MMP-9 release only when PGD ₂ pathway overcame PGE ₂ pathway. Conclusions— These results suggest that COX-2 may have proinflammatory and antiinflammatory properties as a function of expression of downstream PGH ₂ isomerases, and that the switch from L-PGDS to mPGES-1 in plaque macrophages is associated with cerebral ischemic syndromes, possibly through MMP-induced plaque rupture.