Lipoprotein-Derived Lysophosphatidic Acid Promotes Atherosclerosis by Releasing CXCL1 from the Endothelium
Lipoprotein-Derived Lysophosphatidic Acid Promotes Atherosclerosis by Releasing CXCL1 from the Endothelium
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DOI：
10.1016/j.cmet.2011.02.016
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发表时间：
2011-05-04
期刊：
影响因子：
29
通讯作者：
Schobert, Andreas
中科院分区：
文献类型：
--
作者：
Zhou, Zhe;Subramanian, Pallavi;Schobert, Andreas
氧化修饰的低密度脂蛋白(OxLDL)通过增加单核细胞的黏附在动脉粥样硬化的发生中起关键作用。然而，氧化低密度脂蛋白诱导体内致动脉粥样硬化单核细胞募集的机制仍不清楚。低密度脂蛋白氧化生成溶血磷脂酰胆碱，这是溶血磷脂酸(LPA)产生酶自趋化的主要底物。我们发现oxLDL需要内皮LPA受体和自体趋化蛋白来诱导依赖于CXCL1的动脉单核细胞黏附。不饱和LPA释放内皮细胞CXCL1，随后将其固定在细胞表面，并介导LPA诱导的单核细胞黏附。局部和全身应用LPA可加速小鼠动脉粥样硬化的进展。在功能性CXCL1存在的情况下，阻断LPA受体LPA(1)和LPA(3)可减少高脂血症诱导的动脉白细胞停滞和动脉粥样硬化。因此，高脂血症和修饰低密度脂蛋白介导的致动脉粥样硬化单核细胞募集关键依赖于LPA，LPA触发CXCL1的内皮沉积，揭示LPA信号作为心血管疾病治疗的靶点。
Oxidatively modified low-density lipoprotein (oxLDL) plays a key role in the initiation of atherosclerosis by increasing monocyte adhesion. The mechanism that is responsible for the oxLDL-induced atherogenic monocyte recruitment in vivo, however, still remains unknown. Oxidation of LDL generates lysophosphatidylcholine, which is the main substrate for the lysophosphatidic acid (LPA) generating enzyme autotaxin. We show that oxLDL requires endothelial LPA receptors and autotaxin to elicit CXCL1-dependent arterial monocyte adhesion. Unsaturated LPA releases endothelial CXCL1, which is subsequently immobilized on the cell surface and mediates LPA-induced monocyte adhesion. Local and systemic application of LPA accelerates the progression of atherosclerosis in mice. Blocking the LPA receptors LPA(1) and LPA(3) reduced hyperlipidemia-induced arterial leukocyte arrest and atherosclerosis in the presence of functional CXCL1. Thus, atherogenic monocyte recruitment mediated by hyperlipidemia and modified LDL crucially depends on LPA, which triggers endothelial deposition of CXCL1, revealing LPA signaling as a target for cardiovascular disease treatments.