title: Blockade of the angiotensin II type 1 receptor stabilizes atherosclerotic plaques in humans by inhibiting prostaglandin E2-dependent matrix metalloproteinase activity.
abstract: BACKGROUND
  Clinical trials have demonstrated that agents that inhibit the angiotensin II pathway confer benefit beyond the reduction of blood pressure alone. However, the molecular mechanism underlying this effect has yet to be investigated. Recently, we have demonstrated enhanced expression of inducible cyclooxygenase (COX) and prostaglandin (PG)E2-dependent synthase (COX-2/mPGES-1) in human symptomatic plaques and provided evidence that it is associated with metalloproteinase (MMP)-induced plaque rupture. Thus, the aim of this study was to characterize the effect of the angiotensin II type 1 (AT1) receptor antagonist irbesartan on the inflammatory infiltration and expression of COX-2/mPGES-1 and MMPs in human carotid plaques.
  
  
  RESULTS
  Seventy patients with symptomatic carotid artery stenosis were randomized to irbesartan (300 mg/d) or chlorthalidone (50 mg/d) for 4 months before endarterectomy. Plaques were subjected to analysis of COX-1, COX-2, mPGES-1, MMP-2, and MMP-9, angiotensin II, AT(1), AT2, and collagen content by immunocytochemistry, Western blot, and reverse-transcriptase polymerase chain reaction, whereas zymography was used to detect MMP activity. Immunohistochemistry was also used to identify CD68+ macrophages, CD3+ T lymphocytes, smooth muscle cells (SMCs), and HLA-DR+ inflammatory cells. Plaques from the irbesartan group had fewer (P<0.0001) macrophages, T lymphocytes, and HLA-DR+ cells; less (P<0.0001) immunoreactivity for COX-2/mPGES-1 and MMPs; reduced (P<0.0001) gelatinolytic activity; and increased (P<0.0001) collagen content. It is worth noting that COX-2/mPGES-1 inhibition was observed after incubation in vitro with irbesartan but not with the selective AT2 blockade PD123,319.
  
  
  CONCLUSIONS
  This study demonstrates that irbesartan decreases inflammation and inhibits COX-2/mPGES-1 expression in plaque macrophages, and this effect may in turn contribute to plaque stabilization by inhibition of MMP-induced plaque rupture.
authors.affiliation: G. d'Annunzio University of Chieti and the G. d'Annunzio University Foundation, 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: Barbara
authors.initials: B
authors.lastname: Pini
authors.forename: Chiara
authors.initials: C
authors.lastname: Cuccurullo
authors.forename: Mirco
authors.initials: M
authors.lastname: Zucchelli
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: Mariella
authors.initials: M
authors.lastname: De Luca
authors.forename: Raffaella
authors.initials: R
authors.lastname: Muraro
authors.forename: Roberto
authors.initials: R
authors.lastname: Bei
authors.forename: Marco
authors.initials: M
authors.lastname: Bucci
authors.forename: Franco
authors.initials: F
authors.lastname: Cuccurullo
authors.forename: Andrea
authors.initials: A
authors.lastname: Mezzetti
mesh_terms: D000368:Aged; D000803:Angiotensin I / Q000032:analysis; D000804:Angiotensin II / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics; D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use; D001713:Biphenyl Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D002343:Carotid Artery, Internal / Q000737:chemistry / Q000187:drug effects* / Q000473:pathology; D016893:Carotid Stenosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D002752:Chlorthalidone / Q000494:pharmacology / Q000627:therapeutic use; D003094:Collagen / Q000032:analysis; D003131:Combined Modality Therapy; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D003864:Depression, Chemical; D015232:Dinoprostone / Q000037:antagonists & inhibitors*; D016894:Endarterectomy, Carotid; D004790:Enzyme Induction / Q000187:drug effects; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007249:Inflammation; D019746:Intramolecular Oxidoreductases / Q000032:analysis; D000077405:Irbesartan; D007527:Isoenzymes / Q000032:analysis; D008264:Macrophages / Q000473:pathology; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D008565:Membrane Proteins; D000071876:Prostaglandin-E Synthases; D011451:Prostaglandin-Endoperoxide Synthases / Q000032:analysis; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D012422:Rupture, Spontaneous / Q000517:prevention & control; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D007527:Isoenzymes; D061965:Matrix Metalloproteinase Inhibitors; D008565:Membrane Proteins; D011480:Protease Inhibitors; D013777:Tetrazoles; D000804:Angiotensin II; D003094:Collagen; D000803:Angiotensin I; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; D000077405:Irbesartan; D015232:Dinoprostone; D002752:Chlorthalidone