title: Balance between PGD synthase and PGE synthase is a major determinant of atherosclerotic plaque instability in humans.
abstract: 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.
  
  
  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, PPARgamma, IkappaBalpha, NF-kappaB, 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-kappaB 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.
authors.affiliation: Atherosclerosis Prevention Center, University of Chieti G D'Annunzio, School of Medicine, Chieti, Italy. fcipollone@unich.it
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: Giovanni
authors.initials: G
authors.lastname: Ciabattoni
authors.forename: Barbara
authors.initials: B
authors.lastname: Pini
authors.forename: Chiara
authors.initials: C
authors.lastname: Cuccurullo
authors.forename: Sante
authors.initials: S
authors.lastname: Ucchino
authors.forename: Francesco
authors.initials: F
authors.lastname: Spigonardo
authors.forename: Mariella
authors.initials: M
authors.lastname: De Luca
authors.forename: Cesaria
authors.initials: C
authors.lastname: Prontera
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: D016718:Arachidonic Acid / Q000378:metabolism; D002340:Carotid Artery Diseases / Q000150:complications / Q000201:enzymology* / Q000473:pathology / Q000601:surgery; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000502:physiology; D006801:Humans; D020672:I-kappa B Proteins / Q000032:analysis; D007249:Inflammation / Q000201:enzymology*; D019746:Intramolecular Oxidoreductases / Q000502:physiology*; D002546:Ischemic Attack, Transient / Q000209:etiology; D007527:Isoenzymes / Q000032:analysis / Q000502:physiology*; D054834:Lipocalins; D008264:Macrophages / Q000201:enzymology*; D020780:Matrix Metalloproteinase 9 / Q000502:physiology*; D008565:Membrane Proteins; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000032:analysis; D047495:PPAR gamma / Q000032:analysis; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000502:physiology; D000071876:Prostaglandin-E Synthases; D011451:Prostaglandin-Endoperoxide Synthases / Q000032:analysis / Q000502:physiology*; D020521:Stroke / Q000209:etiology
chemical_list: C477819:15-deoxyprostaglandin J2; D020672:I-kappa B Proteins; D007527:Isoenzymes; D054834:Lipocalins; D008565:Membrane Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D047495:PPAR gamma; D000072000:NF-KappaB Inhibitor alpha; D016718:Arachidonic Acid; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D020780:Matrix Metalloproteinase 9; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; D015232:Dinoprostone; D015230:Prostaglandin D2