Novel functions of lectin-like oxidized LDL receptor-1 (LOX-1)

目的：残留样脂蛋白颗粒(RLP)参与动脉粥样硬化的形成，尤其是糖尿病患者的血脂异常，但其受体(S)及其对血管平滑肌细胞(VSMCs)的作用尚不清楚。在这项研究中，我们研究了凝集素样氧化型低密度脂蛋白受体-1(LOX-1)是否作为RLP的受体，以及它在VSMC中的生物学作用。方法：用含抗载脂蛋白A-I和抗载脂蛋白B-100单抗的免疫亲和凝胶从人血浆中分离RLP。结果：稳定表达LOX-1的CHO-K1细胞能摄取DII标记的RLP，野生型CHO-K1细胞不能摄取DII标记的RLP。RLP诱导牛VSMCs(BVSMCs)LOX-1表达和细胞迁移，而LOX-1特异性siRNAs可显著抑制这种表达和细胞迁移。金属蛋白酶抑制剂、表皮生长因子(EGF)受体酪氨酸激酶、肝素结合EGF样生长因子(HB-EGF)、p38丝裂原活化蛋白激酶(P38 MAPK)、MAPK激酶(MEK1)和磷脂酰肌醇3-激酶(PI3K)可显著阻断RLP诱导的BVSMC LOX-1表达和细胞迁移。结论：LOX-1是一种新的RLPs受体。因此，LOX-1介导的RLP摄取可能通过诱导LOX-1表达和VSMC迁移而在动脉粥样硬化形成中发挥重要作用，特别是在餐后高脂血症、糖尿病和代谢综合征的情况下。

Objective : Remnant-like lipoprotein particles (RLPs) have been implicated in atherogenesis especially by diabetic dyslipidemia ; however, their receptor(s) and effects on vascular smooth muscle cells (VSMCs) remain unclear. In this study, we examined if lectin-like oxidized LDL receptor-1 (LOX-1) acts as a receptor for RLPs and its biological effects in VSMCs. Methods : RLPs were isolated from human plasma by immunoaffinity gel containing anti-apolipoprotein A-I and anti-apolipoprotein B-100 monoclonal antibodies.Results : DiI-labeled RLPs were taken up by CHO-K1 cells stably expressing LOX-1 but not by wild-type CHO-K1 cells. RLPs induced LOX-1 expression and cell migration in bovine VSMCs (BVSMCs), which were significantly suppressed by transfection with LOX-1 specific siRNAs. Inhibitors of metalloproteinases, epidermal growth factor (EGF) receptor tyrosine kinase, heparin-binding EGF-like growth factor (HB-EGF), p38 mitogen-activated protein kinase (p38 MAPK), MAPK kinase (MEK1), and phosphoinositide 3-kinase (PI3K) significantly blocked RLP-induced LOX-1 expression and cell migration of BVSMCs.Conclusion : The present study provides direct evidence that LOX-1 is a novel receptor for RLPs in VSMCs. LOX-1-mediated uptake of RLPs may thus play important roles in atherogenesis by inducing LOX-1 expression and VSMC migration especially in the settings of postprandial hyperlipidemia, diabetes and metabolic syndrome.