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

Abstract

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.

Inflammation and the Development of Atherosclerosis

“…Reducing inflammation may therefore be a key mechanism by which statins alter the biology of the plaque and slow disease progression. Statins also reduce reactive oxygen species while increasing interstitial collagen content and promoting SMC maturation 7,[64][65][66][67][68][69] .…”

Reactive Oxygen Species in Inflammation and Tissue Injury

“…The circulating levels of ICAM-1, VCAM-1, and E-Selectin are elevated in hyperlipidemic and hyperglycemic and noninsulin-dependent diabetic-patients in direct correlation with increased oxidative stress (58,69,86,313,352). Reducing oxidative stress by GSH administration or NAC or low-fat diet improved the circulating levels of adhesion molecules (5,57,85,86). All of these reports indicate that increased expression of CAMs induced by oxidative stress can contribute to the pathogenesis of the inflammatory disorders.…”

Percutaneous Coronary Intervention Results in Acute Increases in Oxidized Phospholipids and Lipoprotein(a)

“…[1][2][3][4] In animals, OxLDL within plaques is preferentially depleted in response to regression/antioxidant diets. [5][6][7] In humans, plaque specimens from carotid and coronary arteries are significantly enriched in OxLDL 1,3 and become depleted in OxLDL after treatment with statins. 8 In particular, unstable plaques appear to be preferentially enriched in OxLDL, 9,10 and OxLDL in plasma has been shown to be associated with acute coronary syndromes 9,11,12 and endothelial dysfunction.…”