Oxidized LDL reduces monocyte CCR2 expression through pathways involving peroxisome proliferator-activated receptor γ
Oxidized LDL reduces monocyte CCR2 expression through pathways involving peroxisome proliferator-activated receptor γ
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DOI：
10.1172/jci10052
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发表时间：
2000-09-01
影响因子：
15.9
通讯作者：
Quehenberger, O
中科院分区：
文献类型：
--
作者：
Han, KH;Chang, MK;Quehenberger, O
ccr2介导的单核细胞向血管壁募集在动脉粥样硬化的所有阶段都起着重要作用。在最近的研究中，我们发现脂蛋白可以调节CCR2的表达，并确定天然LDL是一个积极的调节因子。相反，氧化LDL （OxLDL）主要形成于主动脉内膜，降低CCR2表达，促进单核细胞潴留，可能导致单核细胞在血管壁的病理性积聚。我们现在提供的证据表明，OxLDL通过激活可能涉及过氧化物酶体增殖激活受体γ (PPAR γ)的细胞内信号通路来降低单核细胞CCR2的表达。受体介导的脂蛋白颗粒摄取是必需的，并允许外源配体递送到核受体。OxLDL对CCR2表达的抑制是由OxLDL的脂质成分介导的，如氧化亚油酸代谢物9-HODE和13-HODE，已知的PPAR γ激活剂。改良的apoB则没有这种效果。与PPAR γ信号通路的参与一致，BRL49653在体外新分离的人单核细胞和体内循环的小鼠单核细胞中降低了CCR2的表达。这些结果暗示PPAR γ通过氧化脂质抑制CCR2基因表达，这可能有助于保留炎症部位的单核细胞，如动脉粥样硬化病变。
The CCR2-mediated recruitment of monocytes into the vessel wall plays an important role in all stages of atherosclerosis. In recent studies, we have shown that lipoproteins can modulate CCR2 expression and have identified native LDL as a positive regulator. In contrast, oxidized LDL (OxLDL), which is mainly formed in the aortic intima, reduces CCR2 expression, promotes monocyte retention, and may cause pathological accumulation of monocytes in the vessel wall. We now provide evidence that OxLDL reduces monocyte CCR2 expression by activating intracellular signaling pathways that may involve peroxisome proliferator-activated receptor gamma (PPAR gamma). Receptor-mediated uptake of the lipoprotein particle was required and allows for delivery of the exogenous ligand to the nuclear receptor. The suppression of CCR2 expression by OxLDL was mediated by lipid components of OxLDL, such as the oxidized linoleic acid metabolites 9-HODE and 13-HODE, known activators of PPAR gamma. Modified apoB had no such effect. Consistent with a participation of the PPAR gamma signaling pathway, BRL49653 reduced CCR2 expression in freshly isolated human monocytes ex vivo and in circulating mouse monocytes in vivo. These results implicate PPAR gamma in the inhibition of CCR2 gene expression by oxidized lipids, which may help retain monocytes at sites of inflammation, such as the atherosclerotic lesion.