MODIFICATION OF LOW-DENSITY LIPOPROTEIN WITH 4-HYDROXYNONENAL INDUCES UPTAKE BY MACROPHAGES
MODIFICATION OF LOW-DENSITY LIPOPROTEIN WITH 4-HYDROXYNONENAL INDUCES UPTAKE BY MACROPHAGES
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DOI：
10.1161/01.atv.9.4.538
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发表时间：
1989-07-01
期刊：
影响因子：
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通讯作者：
JURGENS, G
中科院分区：
文献类型：
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作者：
HOFF, HF;ONEIL, J;JURGENS, G
有间接证据表明低密度脂蛋白(LDL)的氧化可能参与动脉粥样硬化的发生发展。氧化修饰低密度脂蛋白可能导致内膜巨噬细胞不受调控地摄取低密度脂蛋白，形成泡沫细胞。由于低密度脂蛋白氧化过程中发生的事件的复杂性，我们测试了在脂质过氧化过程中形成的一种主要繁殖产物4-羟基壬烯醛(HNE)直接修饰低密度脂蛋白是否会导致巨噬细胞的脂质负荷。修饰是通过与不同浓度的HNE孵育低密度脂蛋白来完成的，最高可达7.5 mM。当较低浓度的HNE衍生化低密度脂蛋白时，HNE与载脂蛋白B(Apo B)的共价结合、β-氨基对apo B赖氨酸残基的阻断作用以及低密度脂蛋白的相对电泳率均呈浓度依赖性增加。观察到J774细胞系、小鼠腹膜巨噬细胞和平滑肌细胞对修饰的低密度脂蛋白的降解减少。通过与较高浓度的HNE孵育来修饰低密度脂蛋白可导致低密度脂蛋白聚集。这一修饰与巨噬细胞对低密度脂蛋白的降解显著增加有关。油红O染色观察到聚集的HNE修饰的低密度脂蛋白的降解随着培养时间的延长而线性增加，导致这些细胞的脂质负荷和胆固醇的积累。吞噬似乎是通过吞噬发生的，因为细胞松弛素D，一种吞噬的抑制剂，定量地抑制了标记的HNE低密度脂蛋白的摄取和降解。摄取似乎既不是由低密度脂蛋白受体或清道夫受体介导的，因为与过量的低密度脂蛋白或乙酰基低密度脂蛋白竞争未能抑制标记的、聚集的hNE低密度脂蛋白的降解。巨噬细胞对HNE低密度脂蛋白的饱和降解可以部分归因于空间位阻，因为过量的HNE低密度脂蛋白和其他颗粒配体都可以抑制这种降解。这些研究表明，在脂质过氧化过程中形成的低密度脂蛋白与HNE的相互作用可能是导致组织巨噬细胞不受调节地摄取脂蛋白的结构改变的原因。这可以部分解释动脉粥样硬化中的脂质负载或泡沫细胞的形成。
There is indirect evidence that the oxidation of low density lipoprotein (LDL) may be involved in the development of atherosclerosis. Modification of LDL by oxidation may lead to its unregulated uptake by intimal macrophages to form foam cells. Because of the complexity of events occurring during LDL oxidation, we have tested whether LDL modified directly with 4-hydroxynonenal (HNE), a major propagation product formed during lipid peroxidation and known to be present in oxidized LDL, could bring about lipid loading of macrophages. Modification was accomplished by incubating LDL with various concentrations of HNE up to 7.5 mM. When LDL was derivatized with lower concentrations of HNE, concentration-dependent increases were observed in the covalent binding of HNE to apolipoprotein B (apo B), the blockage of the .epsilon.-amino groups on lysine residues of apo B, and the relative electrophoretic mobility of LDL. Decreases were observed in degradation of the modified LDL by the J774 cell line, mouse peritoneal macrophages, and smooth muscle cells. Modification of LDL by incubation with the higher concentrations of HNE resulted in LDL aggregation. This modification was associated with marked increases in the macrophage degradation of LDL. Degradation of aggregated HNE-modified LDL increased linearly with incubation time, leading to lipid loading of these cells as observed by oil red O staining and cholesterol accumulation. Uptake appeared to occur by phagocytosis, since cytochalasin D, an inhibitor of phagocytosis, quantitatively inhibited uptake and degradation of labeled HNE LDL. Uptake did not appear to be mediated by either the LDL receptor or the scavenger receptor, since competition with excess amounts of LDL or acetyl LDL failed to inhibit degradation of labeled, aggregated HNE LDL. Saturation of degradation of HNE LDL by macrophages could be attributed, in part, to steric hindrance, since both excess HNE LDL and other particulate ligands could inhibit this degradation. These studies suggest that interaction of LDL with HNE formed during lipid peroxidation could be responsible for structural modifications leading to unregulated uptake of the lipoprotein by tissue macrophages. This could partially explain lipid loading or foam cell formation in atherosclerosis.