Inhibition of the ubiquitin-proteasome system: a new avenue for atherosclerosis.
BACKGROUND
The ubiquitin-proteasome system (UPS) is thought to be functionally active in atherosclerosis (AS) lesions. Aspirin was found to be a potent inhibitor of the UPS in some tumour studies; however, its effect on AS remains to be demonstrated in vivo.


METHODS
New Zealand rabbits were placed on a normal diet (N) or on a normal diet with aspirin (NI) or on an atherogenic diet without (H) or with aspirin (HI) for 12 weeks. Proteasome activity, concentrations of plasma lipids and levels of peroxidation were determined. Ubiquitin/ubiquitin-conjugates (Ub), IkappaBalpha, phosphorylated IkappaB (pIkappaBalpha) and p65 were investigated by Western blotting or immunochemistry.


RESULTS
Concentrations of plasma lipids and peroxidation levels were higher in H or HI vs. N or NI. Histological analysis showed that atheroma was increased in H. Ub and IkappaBalpha were mainly localised in subendothelium and media vascular smooth muscle cells. Western blots revealed that Ub, IkappaBalpha, and pIkappaBalpha were increased, whereas p65 was lower in HI vs. H. The activity of the 20S proteasome was functionally active in H vs. N, NI or HI, while the 26S proteasome was not affected in any of the groups.


CONCLUSIONS
Aspirin can attenuate the pathogenesis of atheroma formation, the degradation of IkappaBalpha and pIkappaBalpha, and lower the expression of p65, indicating that its therapeutic effects on AS may be via inhibition of the UPS.
Tan
Chunjiang
C
Division of Cardiovascular Pathophysiology Research Centre, Medical College Shantou University, Shantou, Guangdong, China. tchunj@126.com
Li
Yuguang
Y
Tan
Xuerui
X
Pan
Hongxin
H
Huang
Wen
W
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D001011:Aorta / Q000737:chemistry / Q000187:drug effects / Q000473:pathology; D001241:Aspirin / Q000627:therapeutic use*; D050197:Atherosclerosis / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D002784:Cholesterol / Q000097:blood; D004036:Diet, Atherogenic; D004195:Disease Models, Animal; D020672:I-kappa B Proteins / Q000032:analysis; D008055:Lipids / Q000097:blood; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D061988:Proteasome Inhibitors; D011817:Rabbits; D051996:Transcription Factor RelA / Q000032:analysis; D025801:Ubiquitin / Q000037:antagonists & inhibitors*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D020672:I-kappa B Proteins; D008055:Lipids; D061988:Proteasome Inhibitors; D051996:Transcription Factor RelA; D025801:Ubiquitin; D002784:Cholesterol; D001241:Aspirin