Suppression of RAGE as a basis of simvastatin-dependent plaque stabilization in type 2 diabetes.
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.


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-kappaB, 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.
Cuccurullo
Chiara
C
Atherosclerosis, Hypertension and Dyslipidemia Unit, G.d'Annunzio University of Chieti-Pescara, Italy.
Iezzi
Annalisa
A
Fazia
Maria Luigia
ML
De Cesare
Domenico
D
Di Francesco
Andrea
A
Muraro
Raffaella
R
Bei
Roberto
R
Ucchino
Sante
S
Spigonardo
Francesco
F
Chiarelli
Francesco
F
Schmidt
Ann Marie
AM
Cuccurullo
Franco
F
Mezzetti
Andrea
A
Cipollone
Francesco
F
D000368:Aged; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D016893:Carotid Stenosis / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D005947:Glucose / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009195:Peroxidase / Q000235:genetics / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D019821:Simvastatin / Q000494:pharmacology*
D000924:Anticholesteremic Agents; D017127:Glycation End Products, Advanced; D008565:Membrane Proteins; D016328:NF-kappa B; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D019821:Simvastatin; D009195:Peroxidase; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D005947:Glucose