Lipid lowering reduces oxidative stress and endothelial cell activation in rabbit atheroma.
BACKGROUND
Lipid lowering may reduce acute coronary events in patients in part by reducing vascular inflammation. Oxidative stress induces endothelial cell (EC) expression of vascular cell adhesion molecule 1 (VCAM-1) and monocyte chemoattractant protein 1 (MCP-1) and reduces levels of atheroprotective NO, leading to monocyte recruitment and macrophage accumulation. This study tested the hypothesis that lipid lowering decreases oxidative stress and improves EC functions related to inflammatory cell accumulation.


RESULTS
Rabbits consumed an atherogenic diet for 4 months to produce atheroma, followed by a purified chow diet for 16 months. Atherosclerotic aortas from hypercholesterolemic rabbits produced high levels of reactive oxygen species. Oxidized LDL (oxLDL) accumulated in atheroma underlying ECs that overexpress VCAM-1. In contrast, few if any ECs in atheroma stained for endothelial NO synthase (eNOS). Lipid lowering reduced reactive oxygen species production, oxLDL accumulation, and plasma levels of anti-oxLDL IgG. After lipid lowering, VCAM-1 and MCP-1 expression decreased, eNOS expression increased, and ECs exhibited a more normal ultrastructure.


CONCLUSIONS
These results establish that lipid lowering can reduce oxidative stress and EC activation in vivo. These mechanisms may contribute to improvement in endothelial function and plaque stabilization observed clinically.
Aikawa
Masanori
M
Leducq Center for Cardiovascular Research, Department of Medicine, University of California, San Diego, La Jolla, Calif, USA. maikawa@rics.bwh.harvard.edu
Sugiyama
Seigo
S
Hill
Christopher C
CC
Voglic
Sami J
SJ
Rabkin
Elena
E
Fukumoto
Yoshihiro
Y
Schoen
Frederick J
FJ
Witztum
Joseph L
JL
Libby
Peter
P
D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B / Q000378:metabolism; D001161:Arteriosclerosis / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D001323:Autoantibodies / Q000097:blood; D018932:Chemokine CCL2 / Q000378:metabolism; D046508:Culture Techniques; D004036:Diet, Atherogenic; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000648:ultrastructure; D006937:Hypercholesterolemia / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D008055:Lipids / Q000097:blood*; D008077:Lipoproteins, LDL / Q000276:immunology / Q000378:metabolism; D008297:Male; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D018384:Oxidative Stress; D011817:Rabbits; D017382:Reactive Oxygen Species / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; D001323:Autoantibodies; D018932:Chemokine CCL2; D008055:Lipids; D008077:Lipoproteins, LDL; D017382:Reactive Oxygen Species; D019010:Vascular Cell Adhesion Molecule-1; C099252:oxidized low density lipoprotein; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III