Abstract 14142: NPC1L1 Inhibition with Ezetimibe Suppresses Enhanced Formation of Aortic Atherosclerosis 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, the mechanism of enhanced atherogenesis induced by dietary oxysterols has not been explored.
Aim: The aims of this study are to investigate molecular and cellular mechanisms of atherogenesis induced by dietary oxysterols and to examine therapeutic effects of a cholesterol absorption inhibitor ezetimibe.
Methods and Results: ApoE-deficient mice were fed either a control 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. Compared to control-HFD, dietary oxysterol-HFD enhanced the formation of aortic atherosclerosis, macrophage infiltration, lipid accumulation, immunoreactive MCP-1, and activated MMPs in atherosclerotic lesions without affecting plasma lipid levels (Figure). Those effects of oxysterol-HFD were associated with increased gene expression of MCP-1 and interleukin -1. In addition, oxysterol-HFD increased serum markers of monocyte activation and differentiation. We then examined the effects of an NPC1L1 inhibitor, ezetimibe, and found that oral treatment with ezetimibe at 5 mg/kg per day significantly decreased plasma lipid levels and thus suppressed the enhanced atherosclerosis formation, inflammation, MMPs activation, and monocyte activation induced by oxysterol-HFD (Figure).
Conclusions: Increased monocyte-mediated inflammation may play a critical role in the enhanced atherogenesis induced by dietary oxysterols in this murine model. Inhibiting oxysterol absorption by ezetimibe may be a useful therapeutic approach for the treatment of atherosclerosis formation induced by dietary oxysterols.
- © 2010 by American Heart Association, Inc.