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. Methods and 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, AT1, AT 2, 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, F., Fazia, M., Iezzi, A., Pini, B., Cuccurullo, C., Zucchelli, M., et al. (2004). Blockade of the angiotensin II type 1 receptor stabilizes atherosclerotic plaques in humans by inhibiting prostaglandin E-2-dependent matrix metalloproteinase activity. CIRCULATION, 109(12), 1482-1488 [10.1161/01.CIR.0000121735.52471.AC].

Blockade of the angiotensin II type 1 receptor stabilizes atherosclerotic plaques in humans by inhibiting prostaglandin E-2-dependent matrix metalloproteinase activity

BEI, ROBERTO;
2004-01-01

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. Methods and 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, AT1, AT 2, 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.
2004
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore MED/04 - PATOLOGIA GENERALE
English
Con Impact Factor ISI
1 (4 dimethylamino 3 methylbenzyl) 5 diphenylacetyl 4,5,6,7 tetrahydro 1h imidazo[4,5 c]pyridine 6 carboxylic acid; angiotensin 1 receptor; CD3 antigen; CD68 antigen; chlortalidone; collagen; cyclooxygenase 1; cyclooxygenase 2; HLA DR antigen; irbesartan; matrix metalloproteinase; messenger RNA; prostaglandin E2; adult; aged; antiinflammatory activity; article; atherosclerotic plaque; carotid endarterectomy; clinical trial; controlled clinical trial; controlled study; female; human; human tissue; hypertension; immunohistochemistry; internal carotid artery occlusion; macrophage; major clinical study; male; monocyte; priority journal; prostaglandin synthesis inhibition; randomized controlled trial; receptor blocking; reverse transcription polymerase chain reaction; Aged; Angiotensin I; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Biphenyl Compounds; Carotid Artery, Internal; Carotid Stenosis; Chlorthalidone; Collagen; Combined Modality Therapy; Cyclooxygenase 1; Cyclooxygenase 2; Depression, Chemical; Dinoprostone; Endarterectomy, Carotid; Enzyme Induction; Extracellular Matrix; Female; Gene Expression Regulation; Humans; Inflammation; Intramolecular Oxidoreductases; Isoenzymes; Macrophages; Male; Matrix Metalloproteinases; Membrane Proteins; Prostaglandin-Endoperoxide Synthases; Protease Inhibitors; Rupture, Spontaneous; Tetrazoles
Cipollone, F., Fazia, M., Iezzi, A., Pini, B., Cuccurullo, C., Zucchelli, M., et al. (2004). Blockade of the angiotensin II type 1 receptor stabilizes atherosclerotic plaques in humans by inhibiting prostaglandin E-2-dependent matrix metalloproteinase activity. CIRCULATION, 109(12), 1482-1488 [10.1161/01.CIR.0000121735.52471.AC].
Cipollone, F; Fazia, M; Iezzi, A; Pini, B; Cuccurullo, C; Zucchelli, M; De Cesare, D; Ucchino, S; Spigonardo, F; De Luca, M; Muraro, R; Bei, R; Bucci, M; Cuccurullo, F; Mezzetti, A
Articolo su rivista
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/30499
Citazioni
  • ???jsp.display-item.citation.pmc??? 20
  • Scopus ND
  • ???jsp.display-item.citation.isi??? 130
social impact