title: Suppression of RAGE as a basis of simvastatin-dependent plaque stabilization in type 2 diabetes.
abstract: 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.
authors.affiliation: Atherosclerosis, Hypertension and Dyslipidemia Unit, G.d'Annunzio University of Chieti-Pescara, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Cuccurullo
authors.forename: Annalisa
authors.initials: A
authors.lastname: Iezzi
authors.forename: Maria Luigia
authors.initials: ML
authors.lastname: Fazia
authors.forename: Domenico
authors.initials: D
authors.lastname: De Cesare
authors.forename: Andrea
authors.initials: A
authors.lastname: Di Francesco
authors.forename: Raffaella
authors.initials: R
authors.lastname: Muraro
authors.forename: Roberto
authors.initials: R
authors.lastname: Bei
authors.forename: Sante
authors.initials: S
authors.lastname: Ucchino
authors.forename: Francesco
authors.initials: F
authors.lastname: Spigonardo
authors.forename: Francesco
authors.initials: F
authors.lastname: Chiarelli
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Schmidt
authors.forename: Franco
authors.initials: F
authors.lastname: Cuccurullo
authors.forename: Andrea
authors.initials: A
authors.lastname: Mezzetti
authors.forename: Francesco
authors.initials: F
authors.lastname: Cipollone
mesh_terms: 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*
chemical_list: 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