Ezetimibe reduces plaque inflammation in a rabbit model of atherosclerosis and inhibits monocyte migration in addition to its lipid-lowering effect.
OBJECTIVE
Ezetimibe, a selective inhibitor of intestinal cholesterol absorption, might also suppress inflammatory components of atherogenesis. We have studied the effects of ezetimibe on two characteristics of atherosclerotic plaques (infiltrate and fibrosis) and on expression of inflammatory genes in a rabbit model of accelerated atherosclerosis.


METHODS
Femoral atherosclerosis was induced by a combination of endothelial desiccation and atherogenic diet. Animals were randomized to ezetimibe (0.6 mg x kg(-1) x day(-1)), simvastatin (5 mg x kg(-1) x day(-1)), ezetimibe plus simvastatin or no treatment, still on atherogenic diet. A control group of rabbits received normolipidemic diet.


RESULTS
Rabbits fed the normolipidemic diet showed normal plasma lipid levels. Either the normolipidemic diet or drug treatment reduced the intima/media ratio (normolipidemic diet: 22%, ezetimibe: 13%, simvastatin: 27%, ezetimibe + simvastatin: 28%), compared with rabbits with atherosclerosis. Ezetimibe also decreased macrophage content and monocyte chemoattractant protein-1 expression in atherosclerotic lesions. Furthermore, ezetimibe reduced the increased activity of nuclear factor kappaB in peripheral blood leucocytes and plasma C-reactive protein levels in rabbits with atherosclerosis. In THP-1 cells, ezetimibe decreased monocyte chemoattractant protein-1-induced monocyte migration. Importantly, the combination of ezetimibe with simvastatin was associated with a more significant reduction in plaque monocyte/macrophage content and some proinflammatory markers than observed with each drug alone.


CONCLUSIONS
Ezetimibe had beneficial effects both on atherosclerosis progression and plaque stabilization and showed additional anti-atherogenic benefits when combined with simvastatin. Its effect on monocyte migration provides a potentially beneficial action, in addition to its effects on lipids.
Gómez-Garre
D
D
Area de Prevención y Rehabilitación Cardiaca, Lipid Unit, Vascular Biology Research Laboratory, Instituto Cardiovascular, Madrid, Spain. mgomezg.hcsc@salud.madrid.org
Muñoz-Pacheco
P
P
González-Rubio
M L
ML
Aragoncillo
P
P
Granados
R
R
Fernández-Cruz
A
A
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D050197:Atherosclerosis / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001384:Azetidines / Q000494:pharmacology*; D002097:C-Reactive Protein / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects*; D018932:Chemokine CCL2 / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D000069438:Ezetimibe; D005263:Femoral Artery / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D008055:Lipids / Q000097:blood; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008297:Male; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology; D016328:NF-kappa B / Q000378:metabolism; D011817:Rabbits; D019821:Simvastatin / Q000494:pharmacology
D000924:Anticholesteremic Agents; D001384:Azetidines; D018932:Chemokine CCL2; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D018836:Inflammation Mediators; D008055:Lipids; D016328:NF-kappa B; D002097:C-Reactive Protein; D019821:Simvastatin; D000069438:Ezetimibe