Effects of ubiquitin-proteasome system deregulation on the vascular senescence and atherosclerosis process in elderly patients.
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 microg/mg vs 3.2 +/- 0.1.8 microg/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.
Marfella
Raffaele
R
Department of Geriatrics and Metabolic Diseases, Second University of Naples, Italy. raffaele.marfella@unina2.it
Di Filippo
Clara
C
Laieta
Maria Teresa
MT
Vestini
Rosanna
R
Barbieri
Michelangela
M
Sangiulo
Paolo
P
Crescenzi
Basilio
B
Ferraraccio
Franca
F
Rossi
Francesco
F
D'Amico
Michele
M
Paolisso
Giuseppe
G
D000368:Aged; D000375:Aging / Q000502:physiology*; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology; D003094:Collagen / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008875:Middle Aged; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism / Q000502:physiology*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*
D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; C478985:PDRG1 protein, human; D025801:Ubiquitin; C002744:3-nitrotyrosine; D014443:Tyrosine; D003094:Collagen; D020780:Matrix Metalloproteinase 9; D046988:Proteasome Endopeptidase Complex