Blockade of the Angiotensin II Type 1 Receptor Stabilizes Atherosclerotic Plaques in Humans by Inhibiting Prostaglandin E 2 –Dependent Matrix Metalloproteinase Activity

Author:

Cipollone Francesco1,Fazia Maria1,Iezzi Annalisa1,Pini Barbara1,Cuccurullo Chiara1,Zucchelli Mirco1,de Cesare Domenico1,Ucchino Sante1,Spigonardo Francesco1,De Luca Mariella1,Muraro Raffaella1,Bei Roberto1,Bucci Marco1,Cuccurullo Franco1,Mezzetti Andrea1

Affiliation:

1. 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.

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)E 2 -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 (AT 1 ) 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, AT 1 , 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 AT 2 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.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine

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