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CLINICAL RESEARCH

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, MD, PhD^_*,,_*, Michele D'Amico, PhD^,, Clara Di Filippo, PhD^,, Alfonso Baldi, MD, Mario Siniscalchi, MD, PhD^_*, Ferndinando Carlo Sasso, MD, PhD^_*, Michele Portoghese, MD^||, Ornella Carbonara, MD^_*, Basilio Crescenzi, MD^¶, Paolo Sangiuolo, MD^¶, Giovanni Francesco Nicoletti, MD^#, Raffaele Rossiello, MD^_**, Franca Ferraraccio, MD, Federico Cacciapuoti, MD^_*, Mario Verza, MD^_*, Ludovico Coppola, MD^_*, Francesco Rossi, MD^, and Giuseppe Paolisso, MD, PhD^_*,

^_* Department of Geriatrics and Metabolic Diseases
"Centro di Eccellenza Cardiovascolare,"
Department of Experimental Medicine
Department of Biochemistry, Section of Pathology, Second University of Naples, Naples, Italy
^|| Cardiovascular Surgery Unit, Sassari Hospital, Naples, Italy
^¶ Cardiovascular Surgery Unit, Hospital V. Monaldi, Naples, Italy
^# Department of Surgery, Second University of Naples, Naples, Italy
^_** Department of Biochemistry and Biophysics "F. Cedrangolo," Section of Anatomic Pathology, Second University of Naples, Naples, Italy

Manuscript received November 9, 2005; revised manuscript received January 25, 2006, accepted January 29, 2006.

^_* Reprint requests and correspondence: Dr. Raffaele Marfella, Via Emilio Scaglione 141, 80145 Napoli, Italy (Email: raffaele.marfella{at}unina2.it).

OBJECTIVES: 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.

Abbreviations and Acronyms   ELISA = enzyme-linked immunosorbent assay   IkB = inhibitory kappa B   MMP = matrix metalloproteinase   NFkB = nuclear factor kappa B   NO = nitric oxide   PPAR = peroxisome proliferator-activated receptor   TIA = transient ischemic attack   VSMC = vascular smooth muscle cell

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