Published online before print March 22, 2004, doi: 10.1161/01.CIR.0000121735.52471.AC
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(Circulation. 2004;109:1482-1488.)
© 2004 American Heart Association, Inc.
Clinical Investigation and Reports |
Blockade of the Angiotensin II Type 1 Receptor Stabilizes Atherosclerotic Plaques in Humans by Inhibiting Prostaglandin E2–Dependent Matrix Metalloproteinase Activity
From the "G. d’Annunzio" University of Chieti and the "G. d’Annunzio" University Foundation, Chieti, and University of Rome Tor Vergata, Rome (R.B.), Italy.
Correspondence to Andrea Mezzetti, MD, Centro Regionale per la Prevenzione dell’Aterosclerosi, Nuovo Policlinico SS, Annunziata, Via dei Vestini 66, 66013 Chieti, Italy. E-mail mezzetti{at}unich.it
Received July 15, 2003; de novo received October 7, 2003; revision received December 10; accepted December 22, 2003.
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, 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.
Key Words: inflammation • metalloproteinases • plaque • prostaglandins
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