CLINICAL RESEARCH: ATHEROSCLEROSIS
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, Section of Pathology, Second University of Naples, Naples, Italy
"Centro di Eccellenza Cardiovascolare,", Section of Pathology, Second University of Naples, Naples, Italy
Department of Experimental Medicine, Section of Pathology, Second University of Naples, Naples, Italy
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.
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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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