Dietary Cholesterol Oxidation Products Accelerate Plaque Destabilization and Rupture Associated with Monocyte Infiltration/Activation via the MCP-1-CCR2 Pathway in Mouse Brachiocephalic Arteries: Therapeutic Effects of Ezetimibe

Aim: No prior studies have investigated the effects of dietary cholesterol oxidation products (oxysterols) on atherosclerotic plaque destabilization and rupture. We used an atherosclerotic mouse model with histological features similar to those seen in ruptured human plaques to test the hypothesis that (1) dietary oxysterols accelerate plaque destabilization and rupture and (2) a NPC1L1 inhibitor, ezetimibe, has therapeutic effects on these processes. Methods and Results: Advanced atherosclerotic plaques were examined in innominate arteries of ApoE(-/)-mice that were fed either a regular high-fat diet (HFD) or HFD containing oxysterols (oxysterol-HFD; 6.8% of added cholesterol was oxidized) and infused with angiotensin.. Compared with HFD, oxysterol-HFD did not affect plasma lipid levels but did accelerate plaque destabilization and rupture, which was associated with increased monocyte infiltration/activation, monocyte chemoattractant protein-1 (MCP-1) expression, and matrix metalloproteinase (MMP) activity. Dietary oxysterol-induced plaque destabilization and rupture were blunted in ApoE(-/-) CCR2(-/-) mice. Oral treatment with ezetimibe, significantly decreased plasma lipid levels and prevented the acceleration of plaque destabilization and rupture induced by dietary oxysterol. These data indicate a primary role for monocyte-mediated inflammation via the MCP-1-CCR2 pathway and the resultant increase in MMP activity in plaque destabilization and rupture induced by dietary oxysterols in ApoE(-/-) mice. These data also provide a mechanism by which dietary oxysterols are connected with the pathogenesis of plaque destabilization and rupture. Conclusions: These data suggest that inhibition of the absorption of oxysterols by ezetimibe may be useful for the treatment of high-risk patients with high oxysterol intake. J Atheroscler Thromb, 2012; 19: 986-998.