Institute for Molecular Cardiovascular Research, RWTH Aachen University, Germany.
Cell Metab. 2011 May 4;13(5):592-600. doi: 10.1016/j.cmet.2011.02.016.
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.
氧化型低密度脂蛋白（oxLDL）通过增加单核细胞黏附在动脉粥样硬化的起始中起关键作用。然而，导致 oxLDL 诱导体内动脉粥样硬化性单核细胞募集的机制仍不清楚。LDL 的氧化产生溶血磷脂酰胆碱，它是溶血磷脂酸（LPA）生成酶自分泌酶的主要底物。我们表明，oxLDL 需要内皮细胞 LPA 受体和自分泌酶来引发依赖 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。LPA 的局部和全身应用加速了小鼠动脉粥样硬化的进展。在存在功能性 CXCL1 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黏附并减少动脉粥样硬化。因此，由高脂血症和修饰的 LDL 介导的动脉粥样硬化性单核细胞募集严重依赖于 LPA，它触发内皮细胞 CXCL1 的沉积，揭示了 LPA 信号作为心血管疾病治疗的靶点。
