Abstract 14184: NPC1L1 Inhibition with Ezetimibe Prevents Accelerated Plaque Destabilization and Rupture Induced by Dietary Cholesterol Oxidation Products in ApoE-deficient Mice
Background: Dietary cholesterol oxidation products (oxysterols) are known to be absorbed and incorporate into lipoprotein in blood and atherosclerotic lesions and to accelerate the formation of atherosclerosis in animals. However, no prior studies examined the effects of dietary oxysterols on atherosclerotic plaque destabilization and rupture. Aim:The aims of this study are to examine whether dietary oxysterols accelerate plaque destabilization and rupture, and to examine therapeutic effects of ezetimibe.
Methods and Results: ApoE-deficient mice were fed either a regular high-fat diet (control-HFD) or HFD containing oxysterols (oxysterol-HFD; 6.8 % of cholesterol was oxidized) for 8 weeks and infused with angiotensin II for 4 weeks. Compared with control-HFD, oxysterol-HFD did not affect plasma lipid levels, but did accelerate plaque destabilization (macrophage infiltration, fibrous cap thinning and lipid core expansion, Figure A) and increased the number of ruptures (control-HFD= 3.5±0.3; oxysterol-HFD= 4.9±0.5/mouse; P<0.05, Figure B upper panel) in the brachiocephalic arteries. Interestingly, oxysterol-HFD-induced acceleration of rupture was associated with increased activity of matrix metalloproteinases (MMPs) (Figure B lower panel), increased expression of MCP-1, and increased serum levels of monocyte activation markers. We then examined the effects of ezetimibe, and found that oral treatment with ezetimibe at 5 mg/kg per day significantly decreased plasma lipid levels and thus prevented the accelerated plaque destabilization and rupture, MMPs and monocyte activation induced by oxysterol-HFD.
Conclusions: Dietary oxysterols accelerated atherosclerotic plaque destabilization and rupture possibly by increasing monocyte-mediated inflammation and activating MMPs in this model. Inhibition of dietary oxysterol absorption by ezetimibe may be a reasonable therapeutic approach in high-risk patients who overly intake oxysterols.
- © 2010 by American Heart Association, Inc.