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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:2716.)
© 2006 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Suppression of Rage as a Basis of Simvastatin-Dependent Plaque Stabilization in Type 2 Diabetes

Chiara Cuccurullo; Annalisa Iezzi; Maria Luigia Fazia; Domenico De Cesare; Andrea Di Francesco; Raffaella Muraro; Roberto Bei; Sante Ucchino; Francesco Spigonardo; Francesco Chiarelli; Ann Marie Schmidt; Franco Cuccurullo; Andrea Mezzetti; Francesco Cipollone

From Atherosclerosis, Hypertension and Dyslipidemia Unit (C.C., A.I., M.L.F., D.C., A.D., R.M., S.U., F.S., F.C., F.Cuccurullo, A.M., F. Cipollone), "G.d’Annunzio" University of Chieti-Pescara, and the Center for Aging Sciences,"G. d’Annunzio" University Foundation, Chieti-Pescara, Italy; Department of Experimental Medicine and Pathology (R.B.), University of Rome Tor Vergata, School of Medicine, Rome, Italy; Columbia University (A.M.S.), New York, NY.

Correspondence to Francesco Cipollone, Centro per la Prevenzione dell’Aterosclerosi e Centro di Ricerca Clinica, Centro per lo Studio dell’Invecchiamento (Ce.S.I.), Via Colle dell’Ara, 66013 Chieti, Italy. E-mail fcipollone{at}unich.it

Objective— Receptor for advanced glycation end products (AGEs) (RAGE) plays a central role in the process of plaque rupture in diabetic patients. Recently, it has been reported that RAGE may be downregulated by improving glycemic control. In contrast, despite being well known that RAGE may be induced in human vessels in a glucose-independent fashion, also by myeloperoxidase (MPO)-dependent AGE generation, no data exist regarding the possibility of a pharmacological modulation of glucose-independent RAGE generation. Thus, the aim of this study was to characterize the effect of simvastatin on the expression of RAGE and RAGE-dependent plaque-destabilizing genes in human atherosclerotic plaques.

Methods and Results— Seventy type 2 diabetic patients with asymptomatic carotid artery stenosis (>70%) were randomized to American Heart Association (AHA) step 1 diet plus simvastatin (40 mg/d) or AHA step 1 diet alone for 4 months before endarterectomy. Plaque expression of MPO, AGEs, RAGE, NF-B, COX-2, mPGES-1, matrix metalloproteinase (MMP)-2 and MMP-9, lipid and oxidized LDL (oxLDL) content, procollagen 1, and interstitial collagen was analyzed by immunohistochemistry and Western blot; zymography was used to detect MMP activity. Plaques from the simvastatin group had less (P<0.0001) immunoreactivity for MPO, AGEs, RAGE, p65, COX-2, mPGES-1, MMP-2, and MMP-9, lipids and oxLDL; reduced (P<0.0001) gelatinolytic activity; increased (P<0.0001) procollagen 1 and collagen content; and fewer (P<0.0001) macrophages, T-lymphocytes, and HLA-DR+ cells. Of interest, RAGE inhibition by simvastatin, observed not only in plaque sections but also in plaque-derived macrophages, was reverted by addition of AGEs in vitro.

Conclusions— This study supports the hypothesis that simvastatin inhibits plaque RAGE expression by decreasing MPO-dependent AGE generation. This effect in turn might contribute to plaque stabilization by inhibiting the biosynthesis of PGE₂-dependent MMPs, responsible for plaque rupture.

The aim of this study was to characterize the effect of simvastatin on the expression of RAGE and RAGE-dependent plaque-destabilizing genes in human atherosclerotic plaques. We found that simvastatin inhibits macrophage RAGE expression by decreasing myeloperoxidase-dependent AGE generation. This effect in turn might contribute to plaque stabilization by inhibiting the release of PGE₂-dependent MMPs responsible for plaque rupture.

Key Words: diabetes mellitus • metalloproteinases • myeloperoxidase • RAGE • statins

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