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The Ubiquitin-Proteasome System and Inflammatory Activity in Diabetic Atherosclerotic Plaques

Effects of Rosiglitazone Treatment

¹ Department of Geriatrics and Metabolic Diseases, Second University Naples, Naples, Italy
² Cardiovascular Research Center, Second University Naples, Naples, Italy
³ Department of Experimental Medicine, Second University Naples, Naples, Italy
⁴ Department of Biochemistry, Section of Pathology, Second University Naples, Naples, Italy
⁵ Cardiovascular Surgery Unit, Sassari Hospital, Sassari, Italy
⁶ Cardiovascular Unit, Hospital V. Monaldi, Naples, Italy
⁷ Department of Pathology and Medicine, Experimental and Clinical, University of Udine, Udine, Italy
⁸ Department of Surgery, Second University of Naples, Naples, Italy

Address correspondence and reprint requests to Dott. Raffaele Marfella, Via Emilio Scaglione 141, 80145 Napoli, Italy. E-mail: raffaele.marfella{at}unina2.it

Abbreviations: CRP, C-reactive protein; ELISA, enzyme-linked immunosorbent assay; HOMA-IR, homeostasis model assessment of insulin resistance; IB, inhibitor of B; MMP, matrix metalloproteinase; NF, nuclear factor; PPAR, peroxisome proliferator–activated receptor; TNF, tumor necrosis factor

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)- 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)-B, inhibitor of B (IB)-ß, tumor necrosis factor (TNF)-, 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-), and NF-B (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 IB-ß 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-, and NF-B (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 µmol/l). Ubiquitin-proteasome over-activity is associated with enhanced inflammatory reaction and NF-B 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-B-mediated inflammatory pathways.

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