The receptor RAGE as a progression factor amplifying arachidonate-dependent inflammatory and proteolytic response in human atherosclerotic plaques: role of glycemic control.
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.


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-kappaB, 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-kappaB, 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.
Cipollone
Francesco
F
University of Chieti G D'Annunzio School of Medicine , Chieti, Italy.
Iezzi
Annalisa
A
Fazia
Maria
M
Zucchelli
Mirco
M
Pini
Barbara
B
Cuccurullo
Chiara
C
De Cesare
Domenico
D
De Blasis
Giovanni
G
Muraro
Raffaella
R
Bei
Roberto
R
Chiarelli
Francesco
F
Schmidt
Ann Marie
AM
Cuccurullo
Franco
F
Mezzetti
Andrea
A
D000368:Aged; D016718:Arachidonic Acid / Q000378:metabolism; D001161:Arteriosclerosis / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology; D002465:Cell Movement; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D015232:Dinoprostone / Q000096:biosynthesis* / Q000494:pharmacology; D018450:Disease Progression; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000201:enzymology / Q000276:immunology; D019746:Intramolecular Oxidoreductases / Q000032:analysis / Q000378:metabolism; D007527:Isoenzymes / Q000032:analysis / Q000378:metabolism; D008264:Macrophages / Q000201:enzymology / Q000276:immunology; D008297:Male; D020782:Matrix Metalloproteinases / Q000032:analysis / Q000378:metabolism*; D008565:Membrane Proteins; D009000:Monocytes / Q000201:enzymology; D016328:NF-kappa B / Q000378:metabolism; D000071876:Prostaglandin-E Synthases; D011451:Prostaglandin-Endoperoxide Synthases / Q000032:analysis / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000032:analysis / Q000276:immunology / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology
D007527:Isoenzymes; D008565:Membrane Proteins; D016328:NF-kappa B; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D016718:Arachidonic Acid; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D020782:Matrix Metalloproteinases; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; D015232:Dinoprostone