Circulation. 2003;108:1070-1077
Published online before print August 11, 2003, doi: 10.1161/01.CIR.0000086014.80477.0D
Published online before print August 11, 2003, doi: 10.1161/01.CIR.0000086014.80477.0D
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(Circulation. 2003;108:1070.)
© 2003 American Heart Association, Inc.
Clinical Investigation and Reports |
The Receptor RAGE as a Progression Factor Amplifying Arachidonate-Dependent Inflammatory and Proteolytic Response in Human Atherosclerotic Plaques
Role of Glycemic Control
From the University of Chieti "G D’Annunzio" School of Medicine (F. Cipollone, A.I., M.F., M.Z., B.P., C.C., D.D.C., R.M., F. Chiarelli, F. Cuccurullo, A.M.), Chieti, Italy; S. Filippo & Nicola Hospital (G.D.B.), Avezzano, Italy; University of Rome Tor Vergata School of Medicine (R.B.), Rome, Italy; and Columbia University (A.M.S.), New York, NY.
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 March 11, 2003; revision received June 3, 2003; accepted June 6, 2003.
Background— RAGE (receptor for advanced glycation end products [AGEs]) plays a role in diabetic atherosclerosis. Recently, we have demonstrated enhanced expression of cyclooxygenase-2 and PGE synthase-1 (COX-2/mPGES-1) in human symptomatic plaques, and provided evidence that it is associated with metalloproteinase (MMP)-induced plaque rupture. However, the specific transmembrane signaling pathway(s) influencing plaque COX-2/mPGES-1 expression is unknown. The aim of this study was to characterize RAGE expression in human plaques and to correlate it with the inflammatory infiltration, COX-2/mPGES-1 and MMP expression, and with clinical evidence of diabetes.
Methods and Results— Plaques obtained from 60 patients undergoing carotid endarterectomy were divided into diabetic and nondiabetic according to clinical evidence of type 2 diabetes. Plaques were subjected to analysis of RAGE, NF-
B, COX-2/mPGES-1, MMP-2 and MMP-9, lipid and oxidized LDL (oxLDL) content, and collagen content by immunohistochemistry and Western blot, whereas zymography was used to detect MMP activity. Immunohistochemistry was used to identify CD68+ macrophages, CD3+ T-lymphocytes, smooth muscle cells (SMCs), and HLA-DR+ inflammatory cells. Diabetic plaques had more (P<0.0001) macrophages, T-lymphocytes, and HLA-DR+ cells, more (P<0.0001) immunoreactivity for RAGE, activated NF-B, COX-2/mPGES-1, and MMPs, increased (P<0.0001) gelatinolytic activity, reduced (P<0.0001) collagen content, and increased (P<0.0001) lipid and oxLDL content. Interestingly, RAGE, COX-2/mPGES-1, and MMP expression was linearly correlated with plasma level of HbA1c.
Conclusions— In conclusion, this study demonstrates in humans that RAGE overexpression is associated with enhanced inflammatory reaction and COX-2/mPGES-1 expression in diabetic plaque macrophages, and this effect may contribute to plaque destabilization by inducing culprit metalloproteinase expression.
Key Words: diabetes mellitus • plaque • inflammation • prostaglandins • metalloproteinases
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