The ubiquitin-proteasome system and inflammatory activity in diabetic atherosclerotic plaques: Effects of rosiglitazone treatment

Raffaele Marfella, Michele D'Amico, Katherine Esposito, Alfonso Baldi, Clara Di Filippo, Mario Siniscalchi, Ferndinando Carlo Sasso, Michele Portoghese, Francesca Cirillo, Federico Cacciapuoti, Ornella Carbonara, Basilio Crescenzi, Feliciano Baldi, Antonio Ceriello, Giovanni Francesco Nicoletti, Francesco D'Andrea, Mario Verza, Ludovico Coppola, Francesco Rossi, Dario Giugliano

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Abstract

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)-γ 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)-κB, inhibitor of κB (IκB)-β, tumor necrosis factor (TNF)-α, 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-α), and NF-κB (P <0.001); and more markers of oxidative stress (nitrotyrosine and O 2- production) and MMP-9 (P <0.01), along with a lesser collagen content and IκB-β 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-α, and NF-κB (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-κB 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-κB-mediated inflammatory pathways.

Original languageEnglish
Pages (from-to)622-632
Number of pages11
JournalDiabetes
Volume55
Issue number3
Publication statusPublished - Mar 2006

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ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Marfella, R., D'Amico, M., Esposito, K., Baldi, A., Di Filippo, C., Siniscalchi, M., Sasso, F. C., Portoghese, M., Cirillo, F., Cacciapuoti, F., Carbonara, O., Crescenzi, B., Baldi, F., Ceriello, A., Nicoletti, G. F., D'Andrea, F., Verza, M., Coppola, L., Rossi, F., & Giugliano, D. (2006). The ubiquitin-proteasome system and inflammatory activity in diabetic atherosclerotic plaques: Effects of rosiglitazone treatment. Diabetes, 55(3), 622-632.