The ubiquitin-proteasome system and inflammatory activity in diabetic atherosclerotic plaques: effects of rosiglitazone treatment.
The role of ubiquitin-proteasome system in the accelerated atherosclerotic progression of diabetic patients is unclear. We evaluated ubiquitin-proteasome activity in carotid plaques of asymptomatic diabetic and nondiabetic patients, as well as the effect of rosiglitazone, a peroxisome proliferator-activated receptor (PPAR)-gamma activator, in diabetic plaques. Plaques were obtained from 46 type 2 diabetic and 30 nondiabetic patients undergoing carotid endarterectomy. Diabetic patients received 8 mg rosiglitazone (n = 23) or placebo (n = 23) for 4 months before scheduled endarterectomy. Plaques were analyzed for macrophages (CD68), T-cells (CD3), inflammatory cells (HLA-DR), ubiquitin, proteasome 20S activity, nuclear factor (NF)-kappaB, inhibitor of kappaB (IkappaB)-beta, tumor necrosis factor (TNF)-alpha, nitrotyrosine, matrix metalloproteinase (MMP)-9, and collagen content (immunohistochemistry and enzyme-linked immunosorbent assay). Compared with nondiabetic plaques, diabetic plaques had more macrophages, T-cells, and HLA-DR+ cells (P < 0.001); more ubiquitin, proteasome 20S activity (TNF-alpha), and NF-kappaB (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 IkappaB-beta levels (P < 0.001). Compared with placebo-treated plaques, rosiglitazone-treated diabetic plaques presented less inflammatory cells (P < 0.01); less ubiquitin, proteasome 20S, TNF-alpha, and NF-kappaB (P < 0.01); less nitrotyrosine and superoxide anion production (P < 0.01); and greater collagen content (P < 0.01), indicating a more stable plaque phenotype. Similar findings were obtained in circulating monocytes obtained from the two groups of diabetic patients and cultured in the presence or absence of rosiglitazone (7.0 micromol/l). Ubiquitin-proteasome over-activity is associated with enhanced inflammatory reaction and NF-kappaB expression in diabetic plaques. The inhibition of ubiquitin-proteasome activity in atherosclerotic lesions of diabetic patients by rosiglitazone is associated with morphological and compositional characteristics of a potential stable plaque phenotype, possibly by downregulating NF-kappaB-mediated inflammatory pathways.
Marfella
Raffaele
R
Department of Geriatrics and Metabolic Diseases, Second University Naples, Italy. raffaele.marfella@unina2.it
D'Amico
Michele
M
Esposito
Katherine
K
Baldi
Alfonso
A
Di Filippo
Clara
C
Siniscalchi
Mario
M
Sasso
Ferndinando Carlo
FC
Portoghese
Michele
M
Cirillo
Francesca
F
Cacciapuoti
Federico
F
Carbonara
Ornella
O
Crescenzi
Basilio
B
Baldi
Feliciano
F
Ceriello
Antonio
A
Nicoletti
Giovanni Francesco
GF
D'Andrea
Francesco
F
Verza
Mario
M
Coppola
Ludovico
L
Rossi
Francesco
F
Giugliano
Dario
D
D000368:Aged; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007249:Inflammation / Q000209:etiology*; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000502:physiology; D018384:Oxidative Stress; D047495:PPAR gamma / Q000502:physiology; D046988:Proteasome Endopeptidase Complex / Q000502:physiology*; D000077154:Rosiglitazone; D013481:Superoxides / Q000378:metabolism; D045162:Thiazolidinediones / Q000627:therapeutic use*; D025801:Ubiquitin / Q000378:metabolism*
D007004:Hypoglycemic Agents; D016328:NF-kappa B; D047495:PPAR gamma; D045162:Thiazolidinediones; D025801:Ubiquitin; D000077154:Rosiglitazone; D013481:Superoxides; D046988:Proteasome Endopeptidase Complex