title: Increased activity of the ubiquitin-proteasome system in patients with symptomatic carotid disease is associated with enhanced inflammation and may destabilize the atherosclerotic plaque: effects of rosiglitazone treatment.
abstract: OBJECTIVE
  We evaluated ubiquitin-proteasome activity in carotid plaques of asymptomatic and symptomatic patients and the effect of rosiglitazone, a peroxisome proliferator-activated receptor-gamma activator, in symptomatic plaques.
  
  
  BACKGROUND
  The role of the ubiquitin-proteasome system, the major pathway for non-lysosomal intracellular protein degradation in eucaryotic cells, in the progression of atherosclerotic plaque to instability is unclear.
  
  
  METHODS
  Plaques were obtained from 40 symptomatic and 38 asymptomatic patients undergoing carotid endarterectomy. Symptomatic patients received 8 mg rosiglitazone (n = 20) or placebo (n = 20) for 4 months before scheduled endarterectomy. Plaques were analyzed for macrophages (CD68), T-lymphocytes (CD3), inflammatory cells (HLA-DR), ubiquitin-proteasome activity, nuclear factor kappa B (NFkB), inhibitory kappa B (IkB)-beta, nitrotyrosine, matrix metalloproteinase (MMP)-9, and collagen content (immunohistochemistry and enzyme-linked immunosorbent assay).
  
  
  RESULTS
  Compared with asymptomatic plaques, symptomatic plaques had more macrophages, T-lymphocytes, and HLA-DR+ cells (p < 0.001); more ubiquitin-proteasome activity and NFkB (p < 0.001); and more markers of oxidative stress (nitrotyrosine and O2- production) and MMP-9 (p < 0.01) along with a lesser collagen content and IkB-beta levels (p < 0.001). Compared with placebo-treated plaques, rosiglitazone-treated symptomatic plaques presented fewer inflammatory cells (p < 0.01); less ubiquitin, proteasome 20S, and NFkB (p < 0.01); less nitrotyrosine and O2- production (p<0.01); and greater collagen content (p<0.01), indicating a more stable plaque phenotype.
  
  
  CONCLUSIONS
  Ubiquitin-proteasome overactivity is associated with enhanced inflammatory reaction in symptomatic plaques. The inhibition of ubiquitin-proteasome activity in lesions of symptomatic patients by rosiglitazone is associated with plaque stabilization, possibly by down-regulating NFkB-mediated inflammatory pathways.
authors.affiliation: Department of Geriatrics and Metabolic Diseases, Section of Pathology, Second University of Naples, Naples, Italy. raffaele.marfella@unina2.it
authors.forename: Raffaele
authors.initials: R
authors.lastname: Marfella
authors.forename: Michele
authors.initials: M
authors.lastname: D'Amico
authors.forename: Clara
authors.initials: C
authors.lastname: Di Filippo
authors.forename: Alfonso
authors.initials: A
authors.lastname: Baldi
authors.forename: Mario
authors.initials: M
authors.lastname: Siniscalchi
authors.forename: Ferndinando Carlo
authors.initials: FC
authors.lastname: Sasso
authors.forename: Michele
authors.initials: M
authors.lastname: Portoghese
authors.forename: Ornella
authors.initials: O
authors.lastname: Carbonara
authors.forename: Basilio
authors.initials: B
authors.lastname: Crescenzi
authors.forename: Paolo
authors.initials: P
authors.lastname: Sangiuolo
authors.forename: Giovanni Francesco
authors.initials: GF
authors.lastname: Nicoletti
authors.forename: Raffaele
authors.initials: R
authors.lastname: Rossiello
authors.forename: Franca
authors.initials: F
authors.lastname: Ferraraccio
authors.forename: Federico
authors.initials: F
authors.lastname: Cacciapuoti
authors.forename: Mario
authors.initials: M
authors.lastname: Verza
authors.forename: Ludovico
authors.initials: L
authors.lastname: Coppola
authors.forename: Francesco
authors.initials: F
authors.lastname: Rossi
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Paolisso
mesh_terms: D000368:Aged; D002340:Carotid Artery Diseases / Q000188:drug therapy* / Q000276:immunology*; D005260:Female; D006801:Humans; D007249:Inflammation; D008264:Macrophages / Q000276:immunology; D008297:Male; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000502:physiology*; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use*; D043743:Ubiquitin-Protein Ligase Complexes / Q000187:drug effects / Q000502:physiology*
chemical_list: D045162:Thiazolidinediones; D000077154:Rosiglitazone; D043743:Ubiquitin-Protein Ligase Complexes; D046988:Proteasome Endopeptidase Complex