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

Research output: Contribution to journalArticle

77 Citations (Scopus)

Abstract

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 α-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.

Original languageEnglish (US)
Pages (from-to)2132-2139
Number of pages8
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume26
Issue number9
DOIs
StatePublished - Sep 2006

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Carotid Artery Diseases
Proteasome Endopeptidase Complex
Ubiquitin
Apoptosis
Oxidative Stress
Macrophages
Carotid Endarterectomy
NADPH Oxidase
Carotid Stenosis
Metalloproteases
NADP
Immunoblotting
Smooth Muscle Myocytes
Smooth Muscle
Actins
Atherosclerosis
Proteins
Collagen
Staining and Labeling

Keywords

  • Atherosclerosis
  • Carotid plaque
  • Endarterectomy
  • Oxidative stress
  • Proteasome
  • Stroke
  • Ubiquitin

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Dysregulation of the ubiquitin-proteasome system in human carotid atherosclerosis. / Versari, Daniele; Herrmann, Joerg; Gössl, Mario; Mannheim, Dallit; Sattler, Katherine; Meyer, Fredric B.; Lerman, Lilach O; Lerman, Amir.

In: Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 26, No. 9, 09.2006, p. 2132-2139.

Research output: Contribution to journalArticle

Versari, Daniele ; Herrmann, Joerg ; Gössl, Mario ; Mannheim, Dallit ; Sattler, Katherine ; Meyer, Fredric B. ; Lerman, Lilach O ; Lerman, Amir. / Dysregulation of the ubiquitin-proteasome system in human carotid atherosclerosis. In: Arteriosclerosis, Thrombosis, and Vascular Biology. 2006 ; Vol. 26, No. 9. pp. 2132-2139.
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AU - Herrmann, Joerg

AU - Gössl, Mario

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AU - Meyer, Fredric B.

AU - Lerman, Lilach O

AU - Lerman, Amir

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N2 - 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 α-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.

AB - 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 α-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.

KW - Atherosclerosis

KW - Carotid plaque

KW - Endarterectomy

KW - Oxidative stress

KW - Proteasome

KW - Stroke

KW - Ubiquitin

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