title: Overexpression of functionally coupled cyclooxygenase-2 and prostaglandin E synthase in symptomatic atherosclerotic plaques as a basis of prostaglandin E(2)-dependent plaque instability.
abstract: BACKGROUND
  Studies have implicated a role for prostaglandin (PG) E(2)-dependent matrix metalloproteinase (MMP) biosynthesis in the rupture of atherosclerotic plaque. Cyclooxygenase-2 (COX-2) and PGE synthase (PGES) are coregulated in nucleated cells by inflammatory stimuli. The aim of this study was to characterize the expression of COX-2 and PGES in carotid plaques and to correlate it with the extent of inflammatory infiltration and MMP activity and with clinical features of patients' presentation.
  
  
  RESULTS
  Plaques were obtained from 50 patients undergoing carotid endarterectomy and divided into 2 groups (symptomatic and asymptomatic) according to clinical evidence of recent transient ischemic attack or stroke. Plaques were analyzed for COX-2, PGES, MMP-2, and MMP-9 by immunocytochemistry and Western blot, whereas zymography was used to detect MMP activity. Immunocytochemistry was used to identify CD68+ macrophages, CD3+ T lymphocytes, and HLA-DR+ cells. The percentage of macrophage-rich areas was larger (P<0.0001) in symptomatic plaques. COX-2, PGES, and MMPs were detected in all specimens; enzyme concentration, however, was significantly higher in symptomatic plaques. COX-2, PGES, and MMPs were especially noted in shoulders of symptomatic plaques, colocalizing with HLA-DR+ macrophages. All symptomatic plaques contained activated forms of MMPs. Finally, inhibition of COX-2 by NS-398 was accompanied by decreased production of MMPs that was reversed by PGE(2).
  
  
  CONCLUSIONS
  This study demonstrates the colocalization of COX-2 and PGES in symptomatic lesions and provides evidence that synthesis of COX-2 and PGES by activated macrophages is associated with acute ischemic syndromes, possibly through metalloproteinase-induced plaque rupture.
authors.affiliation: University of Chieti, G. D'Annunzio School of Medicine, Chieti, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Cipollone
authors.forename: C
authors.initials: C
authors.lastname: Prontera
authors.forename: B
authors.initials: B
authors.lastname: Pini
authors.forename: M
authors.initials: M
authors.lastname: Marini
authors.forename: M
authors.initials: M
authors.lastname: Fazia
authors.forename: D
authors.initials: D
authors.lastname: De Cesare
authors.forename: A
authors.initials: A
authors.lastname: Iezzi
authors.forename: S
authors.initials: S
authors.lastname: Ucchino
authors.forename: G
authors.initials: G
authors.lastname: Boccoli
authors.forename: V
authors.initials: V
authors.lastname: Saba
authors.forename: F
authors.initials: F
authors.lastname: Chiarelli
authors.forename: F
authors.initials: F
authors.lastname: Cuccurullo
authors.forename: A
authors.initials: A
authors.lastname: Mezzetti
mesh_terms: D000368:Aged; D001161:Arteriosclerosis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D015153:Blotting, Western; D002339:Carotid Arteries / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism*; D018450:Disease Progression; D004789:Enzyme Activation / Q000276:immunology; D005260:Female; D006684:HLA-DR Antigens / Q000096:biosynthesis; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019746:Intramolecular Oxidoreductases / Q000378:metabolism*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008565:Membrane Proteins; D009000:Monocytes / Q000166:cytology / Q000201:enzymology; D000071876:Prostaglandin-E Synthases; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D006684:HLA-DR Antigens; D007527:Isoenzymes; D008565:Membrane Proteins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; D015232:Dinoprostone