高水平的Lp(a; lipoprotein[a])与多种心血管疾病相关联。Lp(a)由附着于纤溶酶原同源物apo(a)的apoB100含有的粒子组成。Lp(a)清除途径尚不明确。我们先前发现纤溶酶原受体PlgRKT (带有C端赖氨酸的纤溶酶原受体)促进了肝细胞中Lp(a)的摄取。在这里，我们旨在进一步界定PlgRKT的作用，并研究另外两个纤溶酶原受体，即A蛋白异质体2（annexin A2）和S100A10（S100钙结合蛋白A10）在Lp(a)的内吞作用中的作用。我们使用人肝癌（HepG2）细胞和单倍体人成纤维样（HAP1）细胞进行纤溶酶原受体的过表达和基因敲除。通过共聚焦显微镜和Western blot检测，观察和计量Lp(a)、LDL(低密度脂蛋白)、apo(a)和内吞物的摄取。在过表达PlgRKT、annexin A2或S100A10的HepG2和HAP1细胞中，Lp(a)和apo(a)的摄取显著增加，但LDL的摄取没有明显变化。相反，在PlgRKT和S100A10敲除的HAP1细胞中，Lp(a)和apo(a)的摄取显著减少。HepG2细胞的表面结合研究表明，PlgRKT的过表达能增加Lp(a)和apo(a)与质膜的结合，但annexin A2和S100A10则调节大泡吞噬作用，过表达这两个蛋白时显著增加了大泡吞噬标记物二聚葡萄糖的摄取，而S100A10的敲除则显著减少了二聚葡萄糖的摄取。根据这些观察结果，我们测试了PI3K (磷脂酰肌醇3激酶)抑制剂对Lp(a)摄取的影响。结果显示浓度依赖性减少，证实Lp(a)的摄取确实通过大泡吞噬作用介导。这些发现揭示了一个涉及多种纤溶酶原受体的Lp(a)内吞途径，这些受体增加了质膜的结合并促进了Lp(a)的大泡吞噬作用。尽管这些发现是在具有局限性的细胞培养模型中得出的，但它们可能具有临床意义，因为用于癌症治疗的PI3K抑制剂和抗抑郁化合物如易普拉敏等可以抑制大泡吞噬作用。

High levels of Lp(a; lipoprotein[a]) are associated with multiple forms of cardiovascular disease. Lp(a) consists of an apoB100-containing particle attached to the plasminogen homologue apo(a). The pathways for Lp(a) clearance are not well understood. We previously discovered that the plasminogen receptor PlgRKT (plasminogen receptor with a C-terminal lysine) promoted Lp(a) uptake in liver cells. Here, we aimed to further define the role of PlgRKT and to investigate the role of 2 other plasminogen receptors, annexin A2 and S100A10 (S100 calcium-binding protein A10) in the endocytosis of Lp(a).Human hepatocellular carcinoma (HepG2) cells and haploid human fibroblast-like (HAP1) cells were used for overexpression and knockout of plasminogen receptors. The uptake of Lp(a), LDL (low-density lipoprotein), apo(a), and endocytic cargos was visualized and quantified by confocal microscopy and Western blotting.The uptake of both Lp(a) and apo(a), but not LDL, was significantly increased in HepG2 and HAP1 cells overexpressing PlgRKT, annexin A2, or S100A10. Conversely, Lp(a) and apo(a), but not LDL, uptake was significantly reduced in HAP1 cells in which PlgRKT and S100A10 were knocked out. Surface binding studies in HepG2 cells showed that overexpression of PlgRKT, but not annexin A2 or S100A10, increased Lp(a) and apo(a) plasma membrane binding. Annexin A2 and S100A10, on the other hand, appeared to regulate macropinocytosis with both proteins significantly increasing the uptake of the macropinocytosis marker dextran when overexpressed in HepG2 and HAP1 cells and knockout of S100A10 significantly reducing dextran uptake. Bringing these observations together, we tested the effect of a PI3K (phosphoinositide-3-kinase) inhibitor, known to inhibit macropinocytosis, on Lp(a) uptake. Results showed a concentration-dependent reduction confirming that Lp(a) uptake was indeed mediated by macropinocytosis.These findings uncover a novel pathway for Lp(a) endocytosis involving multiple plasminogen receptors that enhance surface binding and stimulate macropinocytosis of Lp(a). Although the findings were produced in cell culture models that have limitations, they could have clinical relevance since drugs that inhibit macropinocytosis are in clinical use, that is, the PI3K inhibitors for cancer therapy and antidepressant compounds, that is, imipramine.