Studies on Hyperlipoproteinemic Trait, Especially Plasma Apolipoprotein Mutants, as a Risk Factor for Atherosclerosis

1.利用基因技术从中国仓鼠卵巢细胞中获得了应用蛋白E突变体和脂蛋白代谢突变体E5和E7。它们与从血浆中获得的结果高度一致。我们研究了载脂蛋白E5和载脂蛋白E7在血浆脂蛋白中的分布，以及这些突变体的肝素结合活性。载脂蛋白E5和载脂蛋白E7在极低密度脂蛋白组分中比在高密度脂蛋白组分中更显著。载脂蛋白E7与肝素的相互作用强于载脂蛋白E3。这可能是载脂蛋白E7突变患者发生动脉粥样硬化疾病的机制之一。2.载脂蛋白B和低密度脂蛋白的异常我们分析了高脂蛋白血症患者低密度脂蛋白与低密度脂蛋白受体的亲和力。本研究未发现家族性载脂蛋白B-100缺陷(Arg_&lt；3500；*Gin)。然而，高甘油三酯血症患者的低密度脂蛋白与低密度脂蛋白受体的亲和力很低。低密度脂蛋白富含蛋白质，低密度脂蛋白含量低，…比对照组的低密度脂蛋白小得多。这些结构和功能的异常被药物治疗逆转，强调了治疗高甘油三酯血症对预防动脉粥样硬化的重要性。3.脂蛋白(A)作为动脉粥样硬化的危险因素我们研究了脂蛋白(A)[Lp(A)]与动脉粥样硬化的关系。即使在胆固醇正常的受试者中，血清Lp(A)升高也与动脉粥样硬化有关，并影响其严重程度。虽然有报道称载脂蛋白(A)的大小与血浆Lp(A)浓度呈负相关，但我们发现每种载脂蛋白(A)亚型的Lp(A)值差异很大。我们的结果提示apo E表型可能是影响血浆Lp(A)浓度的其他因素之一。4.载脂蛋白A-1和载脂蛋白A-IV在动脉粥样硬化动物模型中的作用我们建立了兔载脂蛋白A-I和载脂蛋白A-IV的酶免疫分析方法。这些结果表明WHHL-R中胆固醇的反向运输受损。我们研究了重组高密度脂蛋白(r-HDL)在动脉粥样硬化中的作用。注射r-高密度脂蛋白对动脉粥样硬化的形成有轻微的抑制作用，但两者差异均无统计学意义，提示人工和天然载脂蛋白的生理特性可能不同。较少

1.Applipoprotein E Mutants and Lipoprotein MetabolismApo E mutants, E5 and E7, were produced by Chinese hamster ovary cells by means of gene technology. They were highly consistent with those obtained from plasma. We investigated the distribution of apo E5 and apo E7 among the plasma lipoproteins, and the heparin-binding activities of these mutants. Both apo E5 and apo E7 were more prominent in the VLDL fraction than in the HDL fraction. Apo E7 displayd a stronger interaction with heparin than apo E3. This may be one of the mechanisms producing atherosclerotic disease in patients with the apo E7 mutant.2.Abnormalities of Apolipoprotein B and Low Density LipoproteinWe analyzed the binding affinity of LDL from patients with hyperlipoproteinemia to the LDL receptor. Familial defective apo B-100 (Arg_<3500>*Gin) was not found in the present study. However, LDL from patients with hypertriglyceridemia showed a low affinity to the LDL receptor. The LDL was rich in protein, poor in lipids, and … More smaller than LDL from controls. These structural and functional abnormalities were reversed by drug therapy, emphasizing the importance of treating hypertriglyceridemia for the prevention of atherosclerosis.3.Lipoprotein (a) as a Risk Factor for AtherosclerosisWe investigated the association between Lipoprotein (a) [Lp (a) ] and atherosclerosis. Even in normocholesterolemic subjects, elevated serum Lp (a) was linked to atherosclerosis and influenced its severity. While it is reported that there is an inverse relationship between the size of apo (a) and plasma Lp (a) concentrations, we found wide variations of Lp (a) values in each apo (a) isoform. Our results suggested that apo E phenotype may be one of other factors influencing the plasma Lp (a) concentration.4.Apo A-1 and Apo A-IV in animal models for AtherosclerosisWe developed a enzyme immunoassay for rabbit apo A-I and apo A-IV.Watanabe heritable hyperlipidemic rabbit (WHHL-R) caused reduced levels of apo A-I and apo A-IV.The distribution of apo A-IV in WHHL-R was shifted towards the lipoprotein-free pool. These results show an impaired reverse transport of cholesterol in WHHL-R.We investigated the effects of reconstituted high-density lipoprotein (r-HDL) on atherosclerosis. Injection of r-HDL caused slight inhibition of atherogenesis, but neither change was statistically significant, indicating that the physiological properties of artficial and nativelipoproteins may differ. Less