Published Online
on August 19, 2002

A more recent version of this article appeared on September 10, 2002

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Submitted on December 14, 2001
Revised on June 14, 2002
Accepted on June 14, 2002

Lipid Lowering Reduces Oxidative Stress and Endothelial Cell Activation in Rabbit Atheroma

Masanori Aikawa MD, PhD^*, Seigo Sugiyama MD, PhD, Christopher C. Hill BA, Sami J. Voglic MD, Elena Rabkin MD, PhD, Yoshihiro Fukumoto MD, PhD, Frederick J. Schoen MD, PhD, Joseph L. Witztum MD, and Peter Libby MD

From the Leducq Center for Cardiovascular Research, Department of Medicine (M.A., S.S., C.C.H., S.J.V., Y.F., P.L.) and Department of Pathology (E.R., F.J.S.), Brigham and Women's Hospital, Harvard Medical School, Boston, Mass, and Department of Medicine (J.L.W.), University of California, San Diego, La Jolla, Calif.

^* To whom correspondence should be addressed. E-mail: maikawa{at}rics.bwh.harvard.edu.

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.

Methods and 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.

Key words: atherosclerosis • hypercholesterolemia • endothelium • cell adhesion molecules • nitric oxide synthase

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