Apolipoprotein E4 in macrophages enhances atherogenesis in a low density lipoprotein receptor-dependent manner
Apolipoprotein E4 in macrophages enhances atherogenesis in a low density lipoprotein receptor-dependent manner
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DOI：
10.1074/jbc.m610712200
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发表时间：
2007-03-16
影响因子：
4.8
通讯作者：
Maeda, Nobuyo
中科院分区：
文献类型：
--
作者：
Altenburg, Michael;Johnson, Lance;Maeda, Nobuyo
载脂蛋白E （apoE）和低密度脂蛋白受体（LDLr）是公认的动脉粥样硬化的决定因素。在肝细胞中，这两种蛋白均高表达并有助于血浆脂蛋白清除，除此之外，它们还在血管细胞和巨噬细胞中表达。在这项研究中，我们利用表达人apoE亚型和不同水平LDLr表达的小鼠，研究了人apoE亚型和LDLr水平对原代巨噬细胞体外动脉粥样硬化途径和骨髓移植后动脉粥样硬化发展的影响。LDLr表达的增加显著增加了培养巨噬细胞中胆固醇的传递，且含apoE4的脂蛋白的作用比含apoE3的脂蛋白的作用更为突出。相反，在表达apoE4的巨噬细胞中，LDLr表达增加会降低胆固醇外排，而在表达apoE3的巨噬细胞中则不会。此外，apoE3比apoE4更能保护VLDL免受体外氧化。在表达人类apoE4亚型Apoe(4/4) Ldlr（-/-）的Ldlr缺陷小鼠中，与移植无Ldlr细胞的小鼠相比，用表达Ldlr的骨髓细胞代替Ldlr以剂量依赖的方式增加了动脉粥样硬化病变。相比之下，表达人类apoE3亚型的Apoe(3/3) Ldlr（-/-）小鼠的动脉粥样硬化与巨噬细胞Ldlr表达水平没有差异。我们的研究结果表明，巨噬细胞中的apoE4，而不是apoE3，以ldlr依赖的方式促进小鼠动脉粥样硬化斑块的发展，并表明这种相互作用可能有助于apoE4与人类心血管风险增加的关联。
Apolipoprotein E (apoE) and the low density lipoprotein receptor (LDLr) are well recognized determinants of atherosclerosis. In addition to hepatocytes, where both are highly expressed and contribute to plasma lipoprotein clearance, they are expressed in vascular cells and macrophages. In this study, we examined the effects of human apoE isoforms and LDLr levels in atherogenic pathways in primary macrophages ex vivo and atherosclerosis development after bone marrow transfer in vivo using mice expressing human apoE isoformis and different levels of LDLr expression. Increases in LDLr expression significantly increased cholesterol delivery into macrophages in culture, and the effects were more prominent with lipoproteins containing apoE4 than those containing apoE3. Conversely, increased LDLr expression reduced cholesterol efflux in macrophages expressing apoE4 but not in macrophages expressing apoE3. Furthermore, apoE3 protected VLDL from oxidation in vitro more than did apoE4. In LDLr-deficient mice expressing the human apoE4 isoform, Apoe(4/4) Ldlr(-/-), the replacement of bone marrow cells with those expressing LDLr increased atherosclerotic lesions in a dose-dependent manner compared with mice transplanted with cells having no LDLr. In contrast, atherosclerosis in Apoe(3/3) Ldlr(-/-) mice, expressing the human apoE3 isoform, did not differ by the levels of macrophage LDLr expression. Our results demonstrate that apoE4, but not apoE3, in macrophages enhances atherosclerotic plaque development in mice in an LDLr-dependent manner and suggests that this interaction may contribute to the association of apoE4 with an increased cardiovascular risk in humans.