Cell and molecular biological approaches to atherosclerosis in an animal model for familial hypercholesterolemia.

我们报道了小鼠腹膜巨噬细胞具有三种修饰LDL（乙酰化LDL和氧化LDL）受体（BBRC 1989 159p.1375）Arai等人)。本研究检测了兔腹腔巨噬细胞和库普弗细胞中修饰LDL受体的特性。乙酰化LDL与氧化LDL降解实验的交叉竞争分析表明，兔巨噬细胞具有两种修饰的LDL受体；一种对乙酰型LDL有特异性，另一种对氧化型LDL和乙酰型LDL都有特异性。另一方面，兔Kupffer细胞具有特异性识别氧化LDL的受体。然而，在兔Kupffer细胞中不存在乙酰-LDL特异性受体。除了LDL外，我们在体外对HDL进行了氧化修饰。这种修饰导致载脂蛋白A-1在SDS/PAGE上变性，琼脂糖凝胶电泳上负电荷增加。当与巨噬细胞衍生的泡沫细胞孵卵时，天然HDL引起细胞中胆固醇酯的明显外流。然而，氧化HDL对泡沫细胞中胆固醇酯的降低作用减弱。然而，研究表明，接受抗氧化剂普罗布考治疗的患者的HDL几乎不被Cu^<++>氧化。这些结果表明HDL颗粒中的载脂蛋白A-1对泡沫细胞内胆固醇酯的外排至关重要。最后，我们发现氧化LDL的成分之一溶磷脂酰胆碱可以诱导内皮细胞中MCP-1 mRNA的表达。我们现在正在研究这种表达的详细机制。

We have reported that mouse peritoneal macrophages have three of receptors for modified LDL(acetyl and oxidized LDL)(BBRC 1989 159p.1375 Arai et al). In current study,the characteristics of modified LDL receptors in rabbit peritoneal macrophages and Kupffer cells were examined. Cross competition analysis of the degradation assay between acetyl and oxidized LDL indicated that rabbit macrophages have two kinds of modified LDL receptors;one is specific for acetyl LDL,and the other recognizes both oxidized and acetyl LDL.On the other hand,rabbit Kupffer cells have receptor which recognizes oxidized LDL specifically. However,specific receptor for acetyl-LDL does not exist in rabbit Kupffer cellsIn addition to LDL,we performed oxidative modification of HDL in vitro. This modification resulted in denaturation of apo A-1 on SDS/PAGE and increased the negative charge on agarose gel electrophoresis. When incubated with macrophages-derived foam cells,native HDL caused a marked efflux of cholesteryl ester in the cells. However oxidized HDL showed a lessened effect on the decrease of cholesteryl ester in foam cells. Nevertheless it was shown that HDL from patients treated by probucol,an antioxidant,is hardly oxidized by Cu^<++>. These results indicated that apo A-1 in HDL particles is essential for efflux of cholesteryl ester in the foam cells.Finally we found that one of the components of oxidized LDL,lyso-phosphatidylcholine,induced the expression of MCP-1 mRNA in endothelial cells. We are now investigating the detail mechanism of this expression.