Ezetimibe reduces intimal hyperplasia in rabbit jugular vein graft

BackgroundThe selective cholesterol transport inhibitor ezetimibe is widely used to prevent development of atherosclerosis in patients with hypercholesterolemia. However, whether this agent inhibits intimal hyperplasia in autologous vein grafts is unknown. The present study was undertaken to clarify if ezetimibe reduces cell proliferation and intimal hyperplasia in vein grafts.MethodsForty-four rabbits were randomly divided into two groups: one group received ezetimibe (0.6 mg/kg/d), and the control group did not. Ezetimibe administration was started 1 week before rabbits underwent interposition reversed autologous jugular vein grafts. The proliferative cells and apoptotic cells were counted in the vein grafts 14 days after implantation, and changes in acetylcholine-induced relaxation and endothelial intracellular concentration of Ca2+ ([Ca2+]i) were examined at 28 days.ResultsEzetimibe reduced serum cholesterol and triglyceride. There were fewer proliferating cells in the ezetimibe group (5.7% ± 0.2%, n = 7) than in the control group (12.8% ± 0.5%, n = 7; P < .0001) and more apoptotic cells in the ezetimibe group (5.3% ± 0.2%, n = 7) than in the control group (2.3% ± 0.2%, n = 7; P < .0001). Intimal hyperplasia was less in the ezetimibe group (46.1 ± 6.0 μm, n = 7) than in the control group (76.0 ± 2.5 μm, n = 7; P < .01). Acetylcholine-produced endothelium-dependent relaxation was observed only in the ezetimibe group, which was blocked by the nitric oxide (NO) synthase inhibitor Nω-nitro-l-arginine. Acetylcholine increased [Ca2+]i only in the ezetimibe group.ConclusionsEzetimibe reduced cell proliferation and enhanced cell apoptosis, thus inhibiting intimal hyperplasia in rabbit autologous vein grafts. Ezetimibe restored the acetylcholine-induced increase in [Ca2+]i in endothelial cells and improved endothelium-dependent NO-mediated relaxation in the vein graft. Our results suggest that ezetimibe enhances the function of endothelial NO through an increase in endothelial [Ca2+]i, thus reducing vein graft intimal hyperplasia.

Clinical RelevanceIntimal hyperplasia is a major obstacle to patency after vein grafting. Various treatments have been examined to reduce neointimal hyperplasia; however, a standard clinical treatment has not yet been established. We report here that ezetimibe inhibits intimal hyperplasia in rabbit autologous vein grafts. More importantly, we demonstrated that ezetimibe improves acetylcholine-induced endothelium-dependent relaxation by restoring its endothelial cell [Ca2+]i–mobilizing activity in the grafts. The present results suggest that ezetimibe restores agonist-induced endothelial [Ca2+]i mobilization and enhances the function of endothelium-derived nitric oxide, thus reducing intimal hyperplasia in vein grafts. Our results support the notion that ezetimibe helps to prevent intimal hyperplasia in vein grafts.