A secreted soluble form of LR11, specifically expressed in intimal smooth muscle cells, accelerates formation of lipid-laden macrophages
A secreted soluble form of LR11, specifically expressed in intimal smooth muscle cells, accelerates formation of lipid-laden macrophages
复制标题
DOI：
10.1161/atvbaha.106.137091
复制
发表时间：
2007-05-01
影响因子：
8.7
通讯作者：
Saito, Yasushi
中科院分区：
文献类型：
--
作者：
Ohwaki, Kenji;Bujo, Hideaki;Saito, Yasushi
目的-巨噬细胞在动脉粥样硬化早期和进展阶段富含脂质的不稳定斑块形成中发挥关键作用，并与内膜平滑肌细胞（SMCs）相互作用。LR11（也称为sorLA）是低密度脂蛋白受体家族的一员，在内膜SMCs中高度特异性表达，并引起尿激酶型纤溶酶原激活物受体介导的细胞外基质降解。在这里，我们通过动物模型和培养系统研究了分泌的可溶性LR11 （solLR11）是否能增强巨噬细胞的粘附、迁移和脂质积累。方法与结果-免疫组化显示，大鼠动脉球囊剥脱后增厚的内膜中表达了solLR11。在lr11缺陷小鼠中，巨噬细胞对袖带损伤动脉的浸润明显减少。体外THP-1源性巨噬细胞功能分析显示，solLR11 （1 μ g/mL）显著增加THP-1细胞对乙酰化低密度脂蛋白的摄取，并使细胞表面清除受体SR-A水平分别增加1.7倍和2.8倍。在1 μ g/mL时，SolLR11剂量依赖性地使THP-1巨噬细胞的迁移活性和对细胞外基质的粘附活性分别增加2.0倍和2.1倍。solLR11的这些作用几乎完全被中和的抗尿激酶型纤溶酶原激活物受体抗体所抑制。结论-由内膜SMCs分泌的SolLR11通过激活尿激酶型纤溶酶原激活物受体调节巨噬细胞的粘附、迁移和脂质积累。动脉粥样硬化斑块中脂质巨噬细胞的形成可能受内膜SMCs的SolLR11调控。
Objective - Macrophages play a key role in lipid-rich unstable plaque formation and interact with intimal smooth muscle cells (SMCs) in early and progressive stages of atherosclerosis. LR11 (also called sorLA), a member of low-density lipoprotein receptor family, is highly and specifically expressed in intimal SMCs, and causes urokinase-type plasminogen activator receptor-mediated degradation of extracellular matrices. Here we investigated whether the secreted soluble form of LR11 (solLR11) enhances adhesion, migration, and lipid accumulation in macrophages using animal models and cultured systems.Methods and Results - Immunohistochemistry showed solLR11 expression in thickened intima of balloon-denuded rat artery. Macrophage infiltration into the cuff-injured artery was markedly reduced in LR11-deficient mice. In vitro functional assays using THP-1-derived macrophages showed that solLR11 (1 mu g/mL) significantly increased acetylated low-density lipoprotein uptake by THP-1 cells and cell surface levels of scavenger receptor SR-A 1.7- and 2.8-fold, respectively. SolLR11 dose-dependently increased the migration activity of THP-1 macrophages and adhesion to extracellular matrices 2.0- and 2.1-fold, respectively, at 1 mu g/mL. These effects of solLR11 were almost completely inhibited by a neutralizing anti-urokinase-type plasminogen activator receptor antibody.Conclusion - SolLR11, secreted from intimal SMCs, regulates adhesion, migration, and lipid accumulation in macrophages through activation of urokinase-type plasminogen activator receptor. The formation of lipid-laden macrophages in atherosclerotic plaques possibly is regulated by SolLR11 of intimal SMCs.