Details

Autor(en) / Beteiligte

• Marfella, Raffaele
• D’Amico, Michele
• Di Filippo, Clara
• Baldi, Alfonso
• Siniscalchi, Mario
• Sasso, Ferndinando Carlo
• Portoghese, Michele
• Carbonara, Ornella
• Crescenzi, Basilio
• Sangiuolo, Paolo
• Nicoletti, Giovanni Francesco
• Rossiello, Raffaele
• Ferraraccio, Franca
• Cacciapuoti, Federico
• Verza, Mario
• Coppola, Ludovico
• Rossi, Francesco
• Paolisso, Giuseppe

Titel

Increased Activity of the Ubiquitin-Proteasome System in Patients With Symptomatic Carotid Disease Is Associated With Enhanced Inflammation and May Destabilize the Atherosclerotic Plaque

Ist Teil von

• Journal of the American College of Cardiology, 2006-06, Vol.47 (12), p.2444-2455

Ort / Verlag

Elsevier Inc

Erscheinungsjahr

2006

Link zum Volltext

Quelle

Elsevier ScienceDirect Journals

Beschreibungen/Notizen

• 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 Raffaele Marfella, Michele D’Amico, Clara Di Filippo, Alfonso Baldi, Mario Siniscalchi, Ferndinando Carlo Sasso, Michele Portoghese, Ornella Carbonara, Basilio Crescenzi, Paolo Sangiuolo, Giovanni Francesco Nicoletti, Raffaele Rossiello, Franca Ferraraccio, Federico Cacciapuoti, Mario Verza, Ludovico Coppola, Francesco Rossi, Giuseppe Paolisso Compared with asymptomatic plaques, symptomatic plaques had more CD68, CD3, and HLA-DR+ cells; more ubiquitin-proteasome activity and nuclear factor kappa B (NFkB); more markers of oxidative stress and matrix metalloproteinase-9; and lower lesser collagen content and inhibitory kappa B-beta levels. Compared with placebo-treated plaques, rosiglitazone-treated symptomatic plaques presented fewer inflammatory cells; less ubiquitin, proteasome 20S, and NFkB; less oxidative stress; and greater collagen content, indicating a more stable plaque phenotype. Ubiquitin-proteasome overactivity is associated with enhanced inflammatory reaction and NFkB expression in symptomatic plaques. The inhibition of ubiquitin-proteasome activity in atherosclerotic lesions of symptomatic patients by rosiglitazone is associated with plaque stabilization. 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. 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. 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). 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. 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.