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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:1259.)
© 2004 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

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

Francesco Cipollone; Maria Fazia; Annalisa Iezzi; Giovanni Ciabattoni; Barbara Pini; Chiara Cuccurullo; Sante Ucchino; Francesco Spigonardo; Mariella De Luca; Cesaria Prontera; Francesco Chiarelli; Franco Cuccurullo; Andrea Mezzetti

From the Atherosclerosis Prevention Center (F.C., M.F., A.I., B.P., C.C., C.P., F.Chiarelli, F.Cuccurullo, A.M.), and the Department of Experimental and Clinical Surgery (S.U., F.S., M.D.L.), University of Chieti "G D’Annunzio," School of Medicine, and the Department of Drug Science (G.C.), University of Chieti "G D’Annunzio," School of Pharmacy; Chieti, Italy.

Correspondence to Francesco Cipollone, Centro Regionale per la Prevenzione dell’Aterosclerosi, Centro per lo Studio dell’Invecchiamento (Ce.S.I.), Via Colle dell’Ara, 66013 Chieti, Italy. E-mail fcipollone{at}unich.it

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, PPAR, IB, NF-B, and MMP-9 by immunocytochemistry, Western blot, reverse-transcriptase polymerase chain reaction, enzyme immunoassay, and zymography. Prostaglandin E₂ (PGE₂) pathway was significantly prevalent in symptomatic plaques, whereas PGD₂ pathway was overexpressed in asymptomatic ones, associated with NF-B inactivation and MMP-9 suppression. In vitro COX-2 inhibition in monocytes was associated with reduced MMP-9 release only when PGD₂ pathway overcame PGE₂ pathway.

Conclusions— These results suggest that COX-2 may have proinflammatory and antiinflammatory properties as a function of expression of downstream PGH₂ 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.

The aim of this study was to investigate whether the balance between PGD synthase and PGE synthase activity in macrophages could influence the evolution of human atherosclerotic plaque toward instability. Results clearly demonstrate that COX-2 may have proinflammatory or antiinflammatory properties as a function of downstream PGH₂ isomerases expression.

Key Words: COX-2 • PGE synthase • PGD synthase • metalloproteinase • plaque rupture

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