Isoform-specific effects of apolipoprotein E on atherogenesis: gene transduction studies in mice.
Isoform-specific effects of apolipoprotein E on atherogenesis: gene transduction studies in mice.
复制标题
载脂蛋白 E 对动脉粥样硬化形成的异构体特异性影响：小鼠基因转导研究。
DOI：
10.1161/hc4801.100034
复制
发表时间：
2001
期刊：
影响因子：
37.8
通讯作者：
Fazio,S
中科院分区：
文献类型：
--
作者：
Yoshida,H;Hasty,AH;Major,AS;Ishiguro,H;Su,YR;Gleaves,LA;Babaev,VR;Linton,MF;Fazio,S
我们最近使用了一种基于骨髓的基因治疗方法，证明了由巨噬细胞产生的少量逆转录病毒来源的人载脂蛋白E3(ApoE3)对apoE缺陷小鼠的早期动脉粥样硬化具有保护作用。方法与结果在本研究中，我们评估了巨噬细胞来源的apoE3产生的作用是否与其结合细胞膜的能力有关。为此，我们使用了APOE2和apoEcys142，这两个功能失调的人类变体分别与低密度脂蛋白受体或硫酸乙酰肝素蛋白多糖的结合减少。5周龄的载脂蛋白E基因缺陷小鼠接受了由双亲逆转录病毒或载脂蛋白E3、载脂蛋白2或载脂蛋白Ecys142逆转录病毒载体转导的载脂蛋白E−/−骨髓细胞的移植。用ELISA法检测apoE3、apoE2和apoEcys142小鼠骨髓移植后4周血清中人载脂蛋白E水平，8周时分别为55.5±2 0.3、5 0.5±8.7和15.3±7.3μg/dL。在所有组中，胆固醇水平随着年龄的增长而增加，但不受载脂蛋白E表达的影响。ApoE3雄性小鼠的损伤面积(3808±2224μm~2/切片)比对照组(6503±3475μm~2/切片)小40%。而apoEcys142组小鼠的皮损面积显著增加(10320±6128μm2/张)，而apoEcys142小鼠的皮损面积与对照组相似(5991±2771μm2/张)。结论巨噬细胞来源的载脂蛋白E通过受体依赖途径延缓动脉粥样硬化的发展。
BackgroundWe recently used a bone marrow–based gene therapy approach to show that small amounts of retrovirus-derived human apolipoprotein E3 (apoE3) produced by macrophages are protective against early atherosclerosis in apoE-deficient mice.Methods and ResultsIn the present study, we evaluated whether the effect produced by macrophage-derived apoE3 is related to its ability to bind cellular membranes. To this end, we used apoE2 and apoEcys142, dysfunctional human variants with reduced binding to the LDL receptor or to heparan sulfate proteoglycans, respectively. ApoE-deficient mice, 5 weeks of age, received transplants of apoE−/−bone marrow cells transduced with either parental retrovirus or apoE3, apoE2, or apoEcys142 retroviral vectors. Human apoE was detected by ELISA in the serum of apoE3, apoE2, and apoEcys142 mice as early as 4 weeks after bone marrow transplantation, and at 8 weeks, plasma apoE levels were 55.5±20.3, 50.5±8.7, and 15.3±7.3 μg/dL, respectively. In all groups, cholesterol levels increased with age but were not affected by apoE expression. As previously demonstrated, the lesion area in male apoE3 mice (3808±2224 μm2/section) was 40% smaller than that in control mice (6503±3475 μm2/section). In apoE2 mice, however, the lesion area was similar to that of controls (5991±2771 μm2/section), and apoEcys142 mice showed an unexpected and significant increase in lesion size (10 320±6128 μm2/section). Thus, transplantation with marrow transfected with receptor binding–defective apoE variants did not replicate the antiatherogenic effect of apoE3.ConclusionsThese data provide in vivo evidence suggesting that macrophage-derived apoE delays development of atherosclerosis through a receptor-dependent pathway.