title: Association between prostaglandin E receptor subtype EP4 overexpression and unstable phenotype in atherosclerotic plaques in human.
abstract: 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.
  
  
  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.
authors: Atherosclerosis Prevention Center, G.d'Annunzio University of Chieti, Chieti, Italy. fcipollone@unich.it
authors: Francesco
authors: F
authors: Cipollone
authors: Maria Luigia
authors: ML
authors: Fazia
authors: Annalisa
authors: A
authors: Iezzi
authors: Chiara
authors: C
authors: Cuccurullo
authors: Domenico
authors: D
authors: De Cesare
authors: Sante
authors: S
authors: Ucchino
authors: Francesco
authors: F
authors: Spigonardo
authors: Antonio
authors: A
authors: Marchetti
authors: Fiamma
authors: F
authors: Buttitta
authors: Leonardo
authors: L
authors: Paloscia
authors: Marco
authors: M
authors: Mascellanti
authors: Franco
authors: F
authors: Cuccurullo
authors: Andrea
authors: A
authors: Mezzetti
mesh_terms: D000368:Aged; D002340:Carotid Artery Diseases / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000201:enzymology / Q000276:immunology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D010641:Phenotype; D000071876:Prostaglandin-E Synthases; D018078:Receptors, Prostaglandin E / Q000235:genetics* / Q000378:metabolism; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058308:Receptors, Prostaglandin E, EP3 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D015398:Signal Transduction / Q000276:immunology; D020521:Stroke / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014657:Vasculitis / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism
chemical_list: C545635:PTGER1 protein, human; C545644:PTGER2 protein, human; C545647:PTGER3 protein, human; C545650:PTGER4 protein, human; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058308:Receptors, Prostaglandin E, EP3 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D051546:Cyclooxygenase 2; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases