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Effects of Ubiquitin-Proteasome System Deregulation on the Vascular Senescence and Atherosclerosis Process in Elderly Patients

Departments of ¹ Geriatrics and Metabolic Diseases, ² Experimental Medicine, and ³ Clinical, Public and Preventive Medicine, Second University of Naples, Italy.
⁴ Cardiovascular Surgery Unit, Monaldi Hospital, Naples, Italy.

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

Abstract

Background. The role of the ubiquitin-proteasome system in the vascular senescence and atherosclerotic progression of elderly patients is unclear. We evaluated ubiquitin-proteasome activity in carotid plaques of asymptomatic elderly and adult patients.

Methods. Plaques were obtained from 28 elderly and 18 adult patients undergoing carotid endarterectomy. Plaques were analyzed for ubiquitin levels, proteasome 20S activity, p16 and p53, nitrotyrosine, matrix metalloproteinase-9 (MMP-9) and collagen content (immunohistochemistry and enzyme-linked immunosorbent assay). Serial sections were incubated with specific antibodies anti–human leukocyte antigen (HLA)-DR, anti CD68 and anti-CD3.

Results. Compared to plaques obtained from adult patients, plaques of elderly patients had more ubiquitin levels (257.4 ± 118.9 ng/mg vs 110 ± 14.4 ng/mg, p <.001), nitrotyrosine (3.8 ± 0.55 nmol/pg vs 1.1 ± 0.19 nmol/pg, p <.001), p53 and p16 staining (p <.01), and MMP-9 levels (14.6 ± 2.5 µg/mg vs 3.2 ± 0.1.8 µg/mg, p <.001), along with a lesser collagen content (21.9 ± 4.8% vs 7.1 ± 2.8%, p <.05) and less proteasome 20S activity (24.2 ± 6.9 pmol/mg vs 78.4 ± 10.3 pmol/mg, p <.001).

Conclusions. Our data suggest that reduction of proteasome activity promotes vascular cell senescence, thereby contributing to the pathogenesis of human atherosclerosis.

Key Words: Atherosclerosis • Ubiquitin-proteasome