Blockade of the angiotensin II type 1 receptor stabilizes atherosclerotic plaques in humans by inhibiting prostaglandin E2-dependent matrix metalloproteinase activity.
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.
Cipollone
Francesco
F
G. d'Annunzio University of Chieti and the G. d'Annunzio University Foundation, Chieti, Italy.
Fazia
Maria
M
Iezzi
Annalisa
A
Pini
Barbara
B
Cuccurullo
Chiara
C
Zucchelli
Mirco
M
de Cesare
Domenico
D
Ucchino
Sante
S
Spigonardo
Francesco
F
De Luca
Mariella
M
Muraro
Raffaella
R
Bei
Roberto
R
Bucci
Marco
M
Cuccurullo
Franco
F
Mezzetti
Andrea
A
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*
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