oxLDL induces inflammatory responses in vascular smooth muscle cells via urokinase receptor association with CD36 and TLR4
oxLDL induces inflammatory responses in vascular smooth muscle cells via urokinase receptor association with CD36 and TLR4
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DOI：
10.1016/j.yjmcc.2013.11.005
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发表时间：
2014-01-01
影响因子：
5
通讯作者：
Dumler, Inna
中科院分区：
文献类型：
--
作者：
Kiyan, Yulia;Tkachuk, Sergey;Dumler, Inna
动脉粥样硬化的发病机制涉及脂质代谢不平衡和免疫反应失调，最终导致动脉壁慢性炎症。近年来的研究表明，内源性配体，如修饰的血浆脂蛋白，可以触发先天免疫的模式识别受体（PRR）进行细胞和体液反应。潜在的分子途径仍然很少被探索。在这项研究中，我们研究了氧化低密度脂蛋白（oxLDL）对人原发性冠状动脉平滑肌细胞（VSMC）的炎症作用机制。我们发现低浓度的oxLDL启动了动脉粥样硬化信号，触发VSMC向促炎表型的转变。oxLDL破坏VSMC中收缩蛋白和心肌素的表达，引发细胞功能反应的改变，包括促炎分子的表达。oxLDL的作用通过下调多功能尿激酶受体（uPAR）而被消除。在响应oxLDL uPAR时，CD36和TLR4是病原体和内源性配体的两种主要PRR。我们证明uPAR与CD36和TLR4的关联介导了氧化低密度脂蛋白诱导的和nf - kb依赖性的G-CSF和GM-CSF的表达和VSMC收缩蛋白的变化。upar介导的VSMC释放G-CSF和GM-CSF影响巨噬细胞行为和MCP-1的产生。我们为我们的体外研究结果与体内人类动脉粥样硬化组织的功能相关性提供证据。我们的数据表明，uPAR是PRR簇的一部分，在结构和功能上干扰CD36和TLR4，并对内源性致动脉粥样硬化配体做出反应。他们进一步指出了该集群的每个组成部分在介导最终信号模式中的特定功能。(C) 2013 Elsevier Ltd.版权所有。
The pathogenesis of atherosclerosis involves an imbalanced lipid metabolism and a deregulated immune response culminating in chronic inflammation of the arterial wall. Recent studies show that endogenous ligands, such as modified plasma lipoproteins, can trigger pattern recognition receptors (PRR) of innate immunity for cellular and humoral reactions. The underlying molecular pathways remain less explored. In this study, we investigated the mechanisms of inflammatory effects of oxidized low-density lipoproteins (oxLDL) on human primary coronary artery smooth muscle cells (VSMC). We show that already low concentration of oxLDL initiated atherogenic signals triggering VSMC transition to proinflammatory phenotype. oxLDL impaired the expression of contractile proteins and myocardin in VSMC and initiated changes in cell functional responses, including expression of proinflammatory molecules. The effects of oxLDL were abolished by downregulation of the multifunctional urokinase receptor (uPAR). In response to oxLDL uPAR associated with CD36 and TLR4, the two main PRR for both pathogen and endogenous ligands. We demonstrate that uPAR association with CD36 and TLR4 mediated oxLDL-induced and NF-KB-dependent G-CSF and GM-CSF expression and changes in VSMC contractile proteins. uPAR-mediated release of G-CSF and GM-CSF by VSMC affected macrophage behavior and production of MCP-1. We provide evidence for functional relevance of our in vitro findings to in vivo human atherosclerotic tissues. Our data imply uPAR as a part of a PRR cluster interfering structurally and functionally with CD36 and TLR4 and responding to endogenous atherogenic ligands. They further point to specific function of each component of this cluster in mediating the ultimate signaling pattern. (C) 2013 Elsevier Ltd. All rights reserved.