on June 15, 2006
Published online before print June 15, 2006, doi: 10.1161/01.ATV.0000232501.08576.73
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Submitted on March 11, 2006
Accepted on June 2, 2006
Dysregulation of the Ubiquitin-Proteasome System in Human Carotid Atherosclerosis
Daniele Versari ;
From the Divisions of Cardiovascular Diseases (D.V., J.H., M.G., D.M., K.S., L.O.L., A.L.), Neurosurgery (F.B.M.), and Nephrology and Hypertension (L.O.L.), Mayo Clinic College of Medicine, Rochester, Minn.
* To whom correspondence should be addressed. E-mail: lerman.amir{at}mayo.edu.
Objective--The ubiquitin-proteasome system is the principal degradation route of intracellular and oxidized proteins, thus regulating many cellular processes conceivably important for atherosclerosis. The aim of this study was to evaluate the activity of ubiquitin-proteasome system in human carotid artery plaques in relation to oxidative stress and clinical manifestation.
Methods and Results--In carotid endarterectomy specimens from 83 asymptomatic and 94 symptomatic patients, content of ubiquitin, ubiquitin conjugates, matrix metalloproteases, and NADPH-oxidase-p67 was evaluated by immunoblotting; proteolytic proteasome activity by fluorometric assay; single and double immunostaining for ubiquitin conjugates, 3-nitrotyrosine, apoptosis, smooth muscle 
-actin, and macrophage CD-68, as well as Sirius Red staining for collagen were performed. Compared with asymptomatic patients, symptomatic patients showed a more unstable plaque phenotype, an increased degree of apoptosis, a significantly higher ubiquitin conjugates content (17.72±1.36 versus 10.99±1.04; P<0.001), and lower proteasome activity (5.01±0.70 versus 9.41±1.19 nmol AMC/mg protein/min; P<0.01). Ubiquitin conjugates content was directly correlated to NADPH-p67 and degree of apoptosis. Immunostaining revealed colocalization of ubiquitin conjugates and 3-nitrotyrosine, and accumulation of ubiquitin conjugates in smooth muscle cells and macrophages.
Conclusions--In human carotid plaques increased oxidative stress is associated with inhibition of the proteasome activity and accumulation of ubiquitin conjugates, particularly in symptomatic patients. These results suggest a possible role of the ubiquitin-proteasome system in influencing plaque stability.
Key words: atherosclerosis • carotid plaque • endarterectomy • oxidative stress • proteasome • stroke • ubiquitin
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