title: Dysregulation of the ubiquitin-proteasome system in human carotid atherosclerosis.
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.
  
  
  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 alpha-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.
authors.affiliation: Division of Cardiovascular Diseases, Mayo Clinic Rochester, 200 First St SW, Rochester, MN 55905, USA.
authors.forename: Daniele
authors.initials: D
authors.lastname: Versari
authors.forename: Joerg
authors.initials: J
authors.lastname: Herrmann
authors.forename: Mario
authors.initials: M
authors.lastname: Gössl
authors.forename: Dallit
authors.initials: D
authors.lastname: Mannheim
authors.forename: Katherine
authors.initials: K
authors.lastname: Sattler
authors.forename: Fredric B
authors.initials: FB
authors.lastname: Meyer
authors.forename: Lilach O
authors.initials: LO
authors.lastname: Lerman
authors.forename: Amir
authors.initials: A
authors.lastname: Lerman
mesh_terms: D000368:Aged; D017209:Apoptosis; D002340:Carotid Artery Diseases / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D005260:Female; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D002537:Intracranial Arteriosclerosis / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D018384:Oxidative Stress; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: D061988:Proteasome Inhibitors; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex