title: Suppression of the functionally coupled cyclooxygenase-2/prostaglandin E synthase as a basis of simvastatin-dependent plaque stabilization in humans.
abstract: BACKGROUND
  The clinical benefits of statins are attributed to changes in plaque composition that lead to reduced metalloproteinase (MMP) activity and plaque stabilization. However, the molecular mechanism of this effect is unclear. Recently, we demonstrated enhanced expression of isoforms of inducible cyclooxygenase (COX) and PGE synthase (COX-2/mPGES) in human symptomatic plaque and provided evidence that this is associated with MMP-induced plaque rupture. The aim of this study was to characterize the effect of simvastatin on inflammatory infiltration and the expression of COX-2/mPGES and MMPs in human carotid plaques.
  
  
  RESULTS
  Seventy patients with symptomatic carotid artery stenosis were randomized to the American Heart Association Step 1 diet plus simvastatin (40 mg/d) or the American Heart Association Step 1 diet alone for 4 months before endarterectomy. Plaques were subjected to analysis of COX-1, COX-2, mPGES, MMP-2 and MMP-9, lipid and oxidized LDL (oxLDL) content, and collagen content by immunocytochemistry, Western blot, and reverse transcription-polymerase chain reaction, whereas zymography was used to detect MMP activity. Immunocytochemistry was also used to identify CD68+ macrophages, CD3+ T-lymphocytes, smooth muscle cells (SMCs), and HLA-DR+ inflammatory cells. Plaques from the simvastatin group had fewer (P<0.0001) macrophages, T-lymphocytes, and HLA-DR+ cells; less (P<0.0001) immunoreactivity for COX-2/mPGES and MMPs; reduced (P<0.0001) gelatinolytic activity; increased (P<0.0001) collagen content; and reduced (P<0.0001) lipid and oxLDL content. Interestingly, COX-2/mPGES inhibition by simvastatin was completely reversed by mevalonate in vitro.
  
  
  CONCLUSIONS
  This study demonstrates that simvastatin decreases inflammation and inhibits COX-2/mPGES expression in plaque macrophages, and this effect in turn may contribute to plaque stabilization by inhibition of MMP-induced plaque rupture.
authors.affiliation: Department of Medicine and Aging, School of Medicine, University of Chieti G. d'Annunzio, Chieti, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Cipollone
authors.forename: Maria
authors.initials: M
authors.lastname: Fazia
authors.forename: Annalisa
authors.initials: A
authors.lastname: Iezzi
authors.forename: Mirco
authors.initials: M
authors.lastname: Zucchelli
authors.forename: Barbara
authors.initials: B
authors.lastname: Pini
authors.forename: Domenico
authors.initials: D
authors.lastname: De Cesare
authors.forename: Sante
authors.initials: S
authors.lastname: Ucchino
authors.forename: Francesco
authors.initials: F
authors.lastname: Spigonardo
authors.forename: Guido
authors.initials: G
authors.lastname: Bajocchi
authors.forename: Roberto
authors.initials: R
authors.lastname: Bei
authors.forename: Raffaella
authors.initials: R
authors.lastname: Muraro
authors.forename: Luciano
authors.initials: L
authors.lastname: Artese
authors.forename: Adriano
authors.initials: A
authors.lastname: Piattelli
authors.forename: Francesco
authors.initials: F
authors.lastname: Chiarelli
authors.forename: Franco
authors.initials: F
authors.lastname: Cuccurullo
authors.forename: Andrea
authors.initials: A
authors.lastname: Mezzetti
mesh_terms: D000368:Aged; D016893:Carotid Stenosis / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000628:therapy; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D003131:Combined Modality Therapy; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D015232:Dinoprostone / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005109:Extracellular Matrix / Q000737:chemistry / Q000187:drug effects; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D007249:Inflammation / Q000188:drug therapy; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008262:Macrophage Activation; D008264:Macrophages / Q000201:enzymology / Q000276:immunology; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008565:Membrane Proteins; D000071876:Prostaglandin-E Synthases; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology* / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D019821:Simvastatin; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D020782:Matrix Metalloproteinases; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; D015232:Dinoprostone