Oxidative stress-related increase in ubiquitination in early coronary atherogenesis.
The ubiquitin-proteasome system (UPS) is involved in the removal of damaged proteins and the activation of transcription factors, such as nuclear-factor-kappaB. Recent reports, however, questioned the functional activity of the UPS under conditions of increased oxidative stress, such as experimental hypercholesterolemia, which was the objective of our study. Pigs were placed on a normal chow diet (N) or on a hypercholesterolemic diet without (HC) or with vitamin C and E supplementation (HC+VIT) for 12 weeks. Compared with N, plasma concentration of total cholesterol increased in both HC and HC+VIT [76 +/- 21 vs. 400 +/- 148 (P<0.05) and 329 +/- 102 (P<0.05) mg/dL], whereas increase in lipid peroxidation, as assessed by LDL-malondialdehyde plasma concentration, was found in HC but not in HC+VIT [6.6 +/- 0.7 vs. 8.5 +/- 0.3 (P<0.05) and 6.8 +/- 0.7 nmol/mg protein]. In comparison with N, the level of ubiquitin conjugates in the coronary artery, as assessed by immunoblotting, increased by 42% in HC but not in HC+VIT and was localized predominantly to media vascular smooth muscle cells by immunostaining. There was no difference in proteasome proteolytic activity among the study groups. These results demonstrate that the UPS is functionally active in early atherogenesis despite increase in oxidative stress with important repercussions in the pathophysiology and therapy of cardiovascular diseases.
Hermann
Joerg
J
Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN 55905, USA.
Gulati
Rajiv
R
Napoli
Claudio
C
Woodrum
Julie E
JE
Lerman
Lilach O
LO
Rodriguez-Porcel
Martin
M
Sica
Vincenzo
V
Simari
Robert D
RD
Ciechanover
Aaron
A
Lerman
Amir
A
D000818:Animals; D002478:Cells, Cultured; D003324:Coronary Artery Disease / Q000209:etiology / Q000378:metabolism*; D003331:Coronary Vessels / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism; D005260:Female; D006937:Hypercholesterolemia / Q000378:metabolism; D008954:Models, Biological; D009097:Multienzyme Complexes / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D018384:Oxidative Stress; D046988:Proteasome Endopeptidase Complex; D011506:Proteins / Q000378:metabolism; D013552:Swine; D014452:Ubiquitins / Q000378:metabolism*
D009097:Multienzyme Complexes; D011506:Proteins; D014452:Ubiquitins; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex