Activated nuclear factor-kappaB is present in the coronary vasculature in experimental hypercholesterolemia.
BACKGROUND
Experimental hypercholesterolemia (HC) is characterized by a decrease in nitric oxide (NO) bioavailability and cellular proliferation. Nuclear factor-kappaB (NF-kappaB) is a transcriptional factor which plays a coordinating role in inflammation and cellular proliferation and may be involved in early atherosclerosis. We examined whether activated NF-kappaB was present in experimental hypercholesterolemia in the coronary vasculature in association with a decrease in NO bioavailability.


METHODS
A total of 14 juvenile domestic crossbred pigs were placed on a HC diet and six pigs on a normal diet for 10-12 weeks. A monoclonal antibody to the activated form of the p65 subunit of NF-kappaB was used to detect immunoreactivity in coronary artery sections. Coronary tissue homogenates were analyzed for activated NF-kappaB and endothelial nitric oxide synthase (eNOS) using Western blotting. In vitro coronary endothelium-dependent relaxation was performed in response to bradykinin, as a measure of NO bioavailability.


RESULTS
Intimal staining for activated NF-kappaB was present in 12/14 HC pigs as compared with 0/6 controls (P<0.001). Confocal microscopy confirmed the presence of NF-kappaB in the nucleus of intimal cells although the majority of the staining was cytoplasmic. In the HC group, Western blotting revealed an increase in activated NF-kappaB in the vessel wall compared to the normal group, in association with a decrease in the presence of eNOS protein and an attenuated vasorelaxation response to bradykinin.


CONCLUSIONS
This study suggests a potential role for activation of NF-kappaB, in association with a decrease in NO bioavailability, in the initial stages of atherosclerosis in the coronary vasculature.
Wilson
S H
SH
Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA.
Caplice
N M
NM
Simari
R D
RD
Holmes
D R
DR
Carlson
P J
PJ
Lerman
A
A
D000818:Animals; D015153:Blotting, Western; D003331:Coronary Vessels / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D005260:Female; D006937:Hypercholesterolemia / Q000097:blood / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D007150:Immunohistochemistry; D008055:Lipids / Q000097:blood; D016328:NF-kappa B / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism; D013552:Swine
D008055:Lipids; D016328:NF-kappa B; D020033:Protein Isoforms