Published online before print July 14, 2005, doi: 10.1161/01.ATV.0000177814.41505.41
© 2005 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Association Between Prostaglandin E Receptor Subtype EP4 Overexpression and Unstable Phenotype in Atherosclerotic Plaques in Human
From Atherosclerosis Prevention Center (F.C., M.L.F., A.I., C.C., D.D.C., A.M., F.B., F.C., A.M.), "G.d’Annunzio" University of Chieti, and the Clinical Research Center "G. d’Annunzio" University Foundation, Chieti, Italy; Experimental and Clinical Surgery Department (S.U., F.S.), "G. d’Annunzio" University of Chieti, Chieti, Italy; Division of Cardiology (L.P., M.M.), "Spirito Santo" Hospital, Pescara, Italy.
Correspondence to Francesco Cipollone, MD, Centro Regionale per la Prevenzione dell’Aterosclerosi e Centro di Ricerca Clinica, Centro per lo Studio dell’Invecchiamento (Ce.S.I.), Via Colle dell’Ara, 66013 Chieti, Italy. E-mail fcipollone{at}unich.it
Objective— We recently demonstrated that inducible cyclooxygenase/PGE synthase-1 (COX-2/mPGES-1) are overexpressed in symptomatic plaques in association with PGE2-dependent metalloproteinase (matrix metalloproteinase [MMP]) biosynthesis and plaque rupture. However, it is not known which of the 4 PGE2 receptors (EP1–4) mediates macrophage metalloproteinase generation. The aim of this study was to characterize EP1–4 expression in plaques from symptomatic and asymptomatic patients undergoing carotid endarterectomy and correlate it with the extent of inflammatory infiltration, COX-2/mPGES-1 and MMP expression and clinical features of patients’ presentation.
Methods and Results— Plaques were analyzed for COX-2, mPGES-1, EP1–4, MMP-2, and MMP-9 by immunohistochemistry, reverse-transcription polymerase chain reaction and Western blot; zymography was used to detect MMP activity. We observed strong EP4 immunoreactivity, only very weak staining for EP2, and no expression of EP1 and EP3 in atherosclerotic plaques. EP4 was more abundant in MMP-rich symptomatic lesions, whereas EP2 was no different between symptomatic and asymptomatic plaques. Finally, MMP induction by PGE2 in vitro was inhibited by the EP4 antagonist L-161 982, but not by its inactive analog L-161 983 or by the EP2 antagonist AH6809.
Conclusions— This study shows that EP4 overexpression is associated with enhanced inflammatory reaction in atherosclerotic plaques. This effect might contribute to plaque destabilization by inducing culprit metalloproteinase expression.
We investigated which of the 4 PGE2 receptors mediates PGE2-dependent metalloproteinase (MMP) generation in carotid plaques from symptomatic and asymptomatic patients. Only EP4 and EP2 were detected in plaques. EP4 was higher in symptomatic plaques and linearly correlated with MMPs. This study indicates a role for EP4 in PGE2-dependent plaque destabilization.
Key Words: atherosclerosis • metalloproteinases • plaque • prostaglandins • receptors
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