This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 26/9/2132    most recent 01.ATV.0000232501.08576.73v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Versari, D. Articles by Lerman, A. Search for Related Content PubMed PubMed Citation Articles by Versari, D. Articles by Lerman, A. Related Collections Cerebrovascular disease/stroke Apoptosis Pathophysiology Smooth muscle proliferation and differentiation Acute Stroke Syndromes Brain Circulation and Metabolism Carotid Stenosis Carotid endarterectomy Transient Ischemic Attacks Mechanism of atherosclerosis/growth factors

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:2132.)
© 2006 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Dysregulation of the Ubiquitin-Proteasome System in Human Carotid Atherosclerosis

Daniele Versari; Joerg Herrmann; Mario Gössl; Dallit Mannheim; Katherine Sattler; Fredric B. Meyer; Lilach O. Lerman; Amir Lerman

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.

Correspondence to Amir Lerman, Division of Cardiovascular Diseases, Mayo Clinic Rochester, 200 First St SW, Rochester, MN 55905. 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.

We evaluated the ubiquitin-proteasome system in relation to atherosclerosis clinical manifestation. Carotid plaques from patients with symptomatic disease showed accumulation of ubiquitin conjugates and lower proteasome activity, along with increased oxidative stress and apoptosis, as compared with asymptomatic patients. These data suggest a potential interplay between oxidative stress and ubiquitin-proteasome system activity in atherosclerosis pathophysiology.

Key Words: atherosclerosis • carotid plaque • endarterectomy • oxidative stress • proteasome • stroke • ubiquitin

This article has been cited by other articles:

				J. Herrmann, L. O. Lerman, and A. Lerman On to the road to degradation: atherosclerosis and the proteasome Cardiovasc Res, November 14, 2009; (2009) cvp333v2. [Abstract] [Full Text] [PDF]

				K. Stangl and V. Stangl The ubiquitin proteasome pathway and endothelial (dys)function Cardiovasc Res, October 13, 2009; (2009) cvp315v2. [Abstract] [Full Text] [PDF]

				P. Meier, D. Golshayan, E. Blanc, M. Pascual, and M. Burnier Oxidized LDL Modulates Apoptosis of Regulatory T Cells in Patients with ESRD J. Am. Soc. Nephrol., June 1, 2009; 20(6): 1368 - 1384. [Abstract] [Full Text] [PDF]

				J. Herrmann, S. M. Soares, L. O. Lerman, and A. Lerman Potential Role of the Ubiquitin-Proteasome System in Atherosclerosis: Aspects of a Protein Quality Disease J. Am. Coll. Cardiol., May 27, 2008; 51(21): 2003 - 2010. [Abstract] [Full Text] [PDF]

				D. Mannheim, J. Herrmann, D. Versari, M. Gossl, F. B. Meyer, J. P. McConnell, L. O. Lerman, and A. Lerman Enhanced Expression of Lp-PLA2 and Lysophosphatidylcholine in Symptomatic Carotid Atherosclerotic Plaques Stroke, May 1, 2008; 39(5): 1448 - 1455. [Abstract] [Full Text] [PDF]

				T. Fukai Targeting Proteasome Worsens Atherosclerosis Circ. Res., October 26, 2007; 101(9): 859 - 861. [Full Text] [PDF]

				J. Herrmann, A. M. Saguner, D. Versari, T. E. Peterson, A. Chade, M. Olson, L. O. Lerman, and A. Lerman Chronic Proteasome Inhibition Contributes to Coronary Atherosclerosis Circ. Res., October 26, 2007; 101(9): 865 - 874. [Abstract] [Full Text] [PDF]

				A. Kovacs, P. Tornvall, R. Nilsson, J. Tegner, A. Hamsten, and J. Bjorkegren Human C-reactive protein slows atherosclerosis development in a mouse model with human-like hypercholesterolemia PNAS, August 21, 2007; 104(34): 13768 - 13773. [Abstract] [Full Text] [PDF]

				J. Herrmann, L. O. Lerman, and A. Lerman Ubiquitin and Ubiquitin-Like Proteins in Protein Regulation Circ. Res., May 11, 2007; 100(9): 1276 - 1291. [Abstract] [Full Text] [PDF]

				R. Marfella, M. Siniscalchi, M. Portoghese, C. Di Filippo, F. Ferraraccio, C. Schiattarella, B. Crescenzi, P. Sangiuolo, G. Ferraro, S. Siciliano, et al. Morning Blood Pressure Surge as a Destabilizing Factor of Atherosclerotic Plaque: Role of Ubiquitin-Proteasome Activity Hypertension, April 1, 2007; 49(4): 784 - 791. [Abstract] [Full Text] [PDF]