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.
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.
Marfella
Raffaele
R
Department of Geriatrics and Metabolic Diseases, Section of Pathology, Second University of Naples, Naples, Italy. raffaele.marfella@unina2.it
D'Amico
Michele
M
Di Filippo
Clara
C
Baldi
Alfonso
A
Siniscalchi
Mario
M
Sasso
Ferndinando Carlo
FC
Portoghese
Michele
M
Carbonara
Ornella
O
Crescenzi
Basilio
B
Sangiuolo
Paolo
P
Nicoletti
Giovanni Francesco
GF
Rossiello
Raffaele
R
Ferraraccio
Franca
F
Cacciapuoti
Federico
F
Verza
Mario
M
Coppola
Ludovico
L
Rossi
Francesco
F
Paolisso
Giuseppe
G
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*
D045162:Thiazolidinediones; D000077154:Rosiglitazone; D043743:Ubiquitin-Protein Ligase Complexes; D046988:Proteasome Endopeptidase Complex