The pathogenesis of foam cell formation - Modified LDL stimulates uptake of co-incubated LDL via macropinocytosis
The pathogenesis of foam cell formation - Modified LDL stimulates uptake of co-incubated LDL via macropinocytosis
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DOI：
10.1161/01.atv.20.3.773
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发表时间：
2000-03-01
影响因子：
8.7
通讯作者：
Willingham, MC
中科院分区：
文献类型：
--
作者：
Jones, NL;Reagan, JW;Willingham, MC
此前，修饰的低密度脂蛋白被证明可以刺激鸽子巨噬细胞中的巨胞饮作用。同时进行LDL和AcLDL的细胞内运输，用胶体金进行差异标记，以确定LDL的摄取是否通过与刺激泡沫细胞形成的AcLDL不同的途径内化，LDL不会引起泡沫细胞形成。AcLDL和LDL在接近高亲和力结合位点饱和的低浓度（12 μ g/mL）或用于诱导泡沫细胞形成的高浓度（50至150 μ g/mL）脂蛋白下进行。胶体金的分布和共标记的百分比，通过透射电子显微镜观察到的细胞器参与包被坑内吞或巨胞饮。低浓度的LDL与AcLDL同时在巨噬细胞上孵育，主要通过包被小凹内吞作用内化。低浓度AcLDL通过包被小凹内吞和巨胞饮两种途径内化。在较高的脂蛋白浓度（50至150 μ g/mL），AcLDL继续通过巨胞饮内化。有趣的是，在高浓度下，共孵育的LDL的显著部分也通过巨胞饮运输。高脂蛋白浓度下巨胞饮体内化的LDL表明AcLDL刺激的巨胞饮作用可能会增加共孵育脂蛋白的摄入。当I-125-LDL与冷AcLDL一起孵育时，37 ℃时LDL降解加倍，而4 ℃时细胞结合或LDL总结合没有相应增加。这些研究表明，修饰的LDL刺激的巨胞饮作用是共孵育LDL降解增加的机制，可能导致泡沫细胞形成。
Previously, modified LDLs were shown to stimulate macropinocytosis in pigeon macrophages. Simultaneous intracellular trafficking of LDL and AcLDL, differentially labeled with colloidal gold, was done to determine whether uptake of LDL, which does not cause foam cell formation, was internalized via a separate route from AcLDL, which stimulates foam cell formation. AcLDL and LDL were followed at either low (12 mu g/mL) concentrations near the saturation of high affinity binding sites or high (50 to 150 mu g/mL) lipoprotein concentrations used to induce foam cell formation. The colloidal gold distribution and percentage of co-labeling as observed by transmission electron microscopy were determined for organelles involved with coated-pit endocytosis or macropinocytosis. LDL simultaneously incubated with AcLDL on macrophages at the low concentration was predominately internalized via coated-pit endocytosis. AcLDL was internalized via both coated-pit endocytosis and macropinocytosis at low concentration. At higher lipoprotein concentrations (50 to 150 mu g/mL), AcLDL continued to be internalized via macropinocytosis. Interestingly, a significant portion of the co-incubated LDL, at high concentrations, also trafficked via macropinocytosis. LDL internalized by macropinosomes at high lipoprotein concentrations suggests that AcLDL-stimulated macropinocytosis might increase uptake of co-incubated lipoproteins. When I-125-LDL was incubated with cold AcLDL, LDL degradation at 37 degrees C doubled, without a corresponding increase in cell association or total binding of LDL at 4 degrees C. These studies suggest that modified LDL-stimulated macropinocytosis is a mechanism for increased degradation of co-incubated LDL potentially leading to foam cell formation.