依折麦布减少兔颈静脉移植后内膜增生。

Ezetimibe reduces intimal hyperplasia in rabbit jugular vein graft.

机构信息

Division of Vascular Surgery, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya City, Japan.

出版信息

J Vasc Surg. 2012 Dec;56(6):1689-97. doi: 10.1016/j.jvs.2012.05.071. Epub 2012 Aug 1.

DOI:10.1016/j.jvs.2012.05.071

PMID:22857809

Abstract

BACKGROUND

The 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.

METHODS

Forty-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.

RESULTS

Ezetimibe 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.

CONCLUSIONS

Ezetimibe 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.

摘要

背景

选择性胆固醇转运抑制剂依折麦布被广泛用于预防高胆固醇血症患者动脉粥样硬化的发展。然而，该药物是否能抑制自体静脉移植物的内膜增生尚不清楚。本研究旨在阐明依折麦布是否能减少静脉移植物中的细胞增殖和内膜增生。

方法

44 只兔子被随机分为两组：一组给予依折麦布（0.6mg/kg/d），对照组不给予。依折麦布治疗于兔子行颈静脉自体旁路移植前 1 周开始。术后 14 天，计数静脉移植物中的增殖细胞和凋亡细胞，并在 28 天检测乙酰胆碱诱导的舒张和内皮细胞内钙离子浓度([Ca2+]i)的变化。

结果

依折麦布降低了血清胆固醇和甘油三酯。依折麦布组的增殖细胞（5.7%±0.2%，n=7）少于对照组（12.8%±0.5%，n=7；P<.0001），凋亡细胞（5.3%±0.2%，n=7）多于对照组（2.3%±0.2%，n=7；P<.0001）。依折麦布组的内膜增生（46.1±6.0μm，n=7）少于对照组（76.0±2.5μm，n=7；P<.01）。只有依折麦布组观察到乙酰胆碱引起的内皮依赖性舒张，该舒张被一氧化氮（NO）合酶抑制剂 Nω-硝基-l-精氨酸阻断。乙酰胆碱仅增加依折麦布组的[Ca2+]i。

结论

依折麦布减少了细胞增殖，增强了细胞凋亡，从而抑制了兔自体静脉移植物的内膜增生。依折麦布恢复了内皮细胞中乙酰胆碱诱导的[Ca2+]i增加，并改善了静脉移植物中内皮细胞一氧化氮（NO）介导的舒张。我们的结果表明，依折麦布通过增加内皮细胞[Ca2+]i增强内皮细胞一氧化氮（NO）的功能，从而减少静脉移植物的内膜增生。