Ezetimibe, a potent cholesterol absorption inhibitor, inhibits the development of atherosclerosis in ApoE knockout mice
Ezetimibe, a potent cholesterol absorption inhibitor, inhibits the development of atherosclerosis in ApoE knockout mice
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DOI：
10.1161/hq1201.100260
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发表时间：
2001-12-01
影响因子：
8.7
通讯作者：
Tetzloff, G
中科院分区：
文献类型：
--
作者：
Davis, HR;Compton, DS;Tetzloff, G
依折麦布（SCH 58235）是一种强效、选择性胆固醇吸收抑制剂。本研究的目的是确定依折麦布是否能降低载脂蛋白E基因敲除（apoE-/-）小鼠的血浆胆固醇并抑制动脉粥样硬化形成。在apoE-/-小鼠中，依折麦布剂量>3 mg/kg时，胆固醇吸收抑制> 90%。在apoE-/-小鼠中测定动脉粥样硬化和脂蛋白变化，这些小鼠喂食高脂肪（0.15%胆固醇）“西方”饮食、低脂（0.15%胆固醇）饮食或半合成无胆固醇饮食（含或不含依折麦布（5 mg/kg/天））6个月。依折麦布使西方饮食组、低脂饮食组和无胆固醇饮食组的血浆胆固醇水平分别从964 mg/dL降至374 mg/dL、从726 mg/dL降至231 mg/dL和从516 mg/dL降至178 mg/dL。极低密度脂蛋白和低密度脂蛋白组分降低，而依折麦布治疗后高密度脂蛋白胆固醇水平升高。依折麦布使西方饮食组的主动脉粥样硬化病变表面积从20.2%降至4.1%，使低脂胆固醇饮食组的主动脉粥样硬化病变表面积从24.1%降至7.0%。依折麦布可使西方和低脂胆固醇组的颈动脉粥样硬化病变横截面积减少97%，使无胆固醇组的颈动脉粥样硬化病变横截面积减少91%。依折麦布可抑制apoE-/-小鼠在西方、低脂和无胆固醇饮食条件下的胆固醇吸收，降低血浆胆固醇，增加高密度脂蛋白水平，并抑制动脉粥样硬化进展。尽管apoE-/-小鼠的高胆固醇血症比人类更严重，并且依折麦布降低低密度脂蛋白的作用在临床上并不明显，但依折麦布可能抑制摄入限脂饮食或西方饮食的个体的动脉粥样硬化形成。
Ezetimibe (SCH58235) is a potent, selective, cholesterol absorption inhibitor. The objective of this study was to determine whether ezetimibe reduces plasma cholesterol and inhibits atherogenesis in apolipoprotein E knockout (apoE-/-) mice. Cholesterol absorption was inhibited by > 90% at doses of ezetimibe >3 mg/kg in apoE-/- mice. Atherosclerosis and lipoprotein changes were determined in apoE-/- mice fed a high-fat (0.15% cholesterol) "western" diet, a low-fat (0.15% cholesterol) diet, or a semisynthetic cholesterol-free diet with or without ezetimibe (5 mg/kg per day) for 6 months. Ezetimibe reduced plasma cholesterol levels from 964 to 374 mg/dL, from 726 to 231 mg/dL, and from 516 to 178 mg/dL in the western, low-fat, and cholesterol-free diet groups, respectively. The reductions occurred in the very low density and low density lipoprotein fractions, whereas high density lipoprotein cholesterol levels were increased by ezetimibe treatment. Ezetimibe reduced aortic atherosclerotic lesion surface area from 20.2% to 4.1% in the western diet group and from 24.1% to 7.0% in the low-fat cholesterol diet group. Ezetimibe reduced carotid artery atherosclerotic lesion cross-sectional area by 97% in the western and low-fat cholesterol groups and by 91% in the cholesterol-free group. Ezetimibe inhibits cholesterol absorption, reduces plasma cholesterol, increases high density lipoprotein levels, and inhibits the progression of atherosclerosis under western, low-fat, and cholesterol-free dietary conditions in apoE-/- mice. Although apoE-/- mice are more hypercholesterolemic than are humans and low density lipoprotein reductions with ezetimibe are not as pronounced clinically, ezetimibe may inhibit atherogenesis in individuals consuming restricted-fat or western diets.