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Lipid lowering reduces oxidative stress and endothelial cell activation in rabbit atheroma
Masanori Aikawa1, Seigo Sugiyama, Christopher C Hill
1Leducq Center for Cardiovascular Research, Department of Medicine, University of California, San Diego, La Jolla, Calif, USA. maikawa@rics.bwh.harvard.edu
Insights
Lipid lowering reduces oxidative stress and endothelial cell activation, decreasing vascular inflammation. This improves endothelial function and plaque stability, potentially lowering acute coronary events.
Area of Science:
- Cardiovascular Science
- Molecular Biology
- Pathophysiology
Background:
- Lipid lowering therapies may mitigate acute coronary events by reducing vascular inflammation.
- Oxidative stress promotes endothelial dysfunction, characterized by increased VCAM-1 and MCP-1 expression and reduced nitric oxide (NO), leading to monocyte recruitment.
- This study investigated the impact of lipid lowering on oxidative stress and endothelial cell (EC) function in an atherosclerosis model.
Purpose of the Study:
- To test the hypothesis that lipid lowering decreases oxidative stress.
- To determine if lipid lowering improves EC functions related to inflammatory cell accumulation.
Main Methods:
- Rabbits were fed an atherogenic diet to induce atheroma, followed by a lipid-lowering diet.
- Assessed reactive oxygen species (ROS) production, oxidized LDL (oxLDL) accumulation, VCAM-1, MCP-1, and endothelial NO synthase (eNOS) expression in atherosclerotic aortas.
- Evaluated EC ultrastructure post-lipid lowering.
Main Results:
- Hypercholesterolemic rabbits exhibited high ROS production, oxLDL accumulation, and VCAM-1 overexpression in ECs.
- Lipid lowering significantly reduced ROS, oxLDL, and inflammatory markers (VCAM-1, MCP-1).
- Endothelial NO synthase (eNOS) expression increased, and ECs showed improved ultrastructure after lipid lowering.
Conclusions:
- Lipid lowering effectively reduces oxidative stress and EC activation in vivo.
- These mechanisms likely contribute to the clinical benefits of lipid lowering, including improved endothelial function and plaque stabilization.
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.
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