Sergio Fazio and MacRae F. Linton are at the Department of Medicine, Division of Endocrinology, Vanderbilt University, School of Medicine, Nashville, TN 37232-6303, USA.
Trends Cardiovasc Med. 1996 Feb;6(2):58-65. doi: 10.1016/1050-1738(96)00007-2.
In recent years, the development of transgenic and gene targeting technologies have made the mouse a powerful model to dissect the contribution of various genes to lipoprotein metabolism and atherosclerosis susceptibility. Here, murine bone marrow transplantation (BMT) is presented as a method to investigate the role of the macrophage in lipoprotein metabolism and atherosclerosis. This approach has been successfully implemented in apolipoprotein (apo) E-deficient mice, which develop severe hyperlipidemia and extensive aortic and coronary atherosclerosis. BMT was performed as a way to deliver macrophages with the normal complement of the apoE gene to the apoE-deficient mice. BMT resulted in the appearance of apoE in plasma, in a sustained drop in cholesterol levels, and in the normalization of the lipoprotein profile. In addition, BMT protected the apoE-deficient mice from diet-induced hypercholesterolemia and atherosclerosis. These data demonstrate that extrahepatic apoE secreted into the plasma compartment is functionally active and promotes lipoprotein clearance, and establish BMT as a novel approach to dissecting the role of macrophages in atherosclerosis and lipid metabolism. In addition, these findings show that the liver is not the obligatory target organ in gene therapy of dyslipidemia, and suggest the use of the macrophage as a vehicle.
近年来，转基因和基因靶向技术的发展使小鼠成为研究各种基因对脂蛋白代谢和动脉粥样硬化易感性的贡献的强大模型。这里介绍了骨髓移植（BMT）作为研究巨噬细胞在脂蛋白代谢和动脉粥样硬化中的作用的一种方法。这种方法已成功应用于载脂蛋白（apo）E 缺陷小鼠，这些小鼠会发生严重的高脂血症和广泛的主动脉和冠状动脉粥样硬化。BMT 是一种将具有正常 apoE 基因组成的巨噬细胞输送到 apoE 缺陷小鼠体内的方法。BMT 导致 apoE 出现在血浆中，胆固醇水平持续下降，脂蛋白谱正常化。此外，BMT 还可防止 apoE 缺陷小鼠发生饮食诱导的高胆固醇血症和动脉粥样硬化。这些数据表明，分泌到血浆中的肝外 apoE 具有功能活性，并促进脂蛋白清除，从而确立了 BMT 作为研究巨噬细胞在动脉粥样硬化和脂质代谢中的作用的新方法。此外，这些发现表明肝脏不是脂质代谢异常基因治疗的必需靶器官，并提示使用巨噬细胞作为载体。
