LRP1B attenuates the migration of smooth muscle cells by reducing membrane localization of urokinase and PDGF receptors
LRP1B attenuates the migration of smooth muscle cells by reducing membrane localization of urokinase and PDGF receptors
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DOI：
10.1161/01.atv.0000133607.80554.09
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发表时间：
2004-08-01
影响因子：
8.7
通讯作者：
Saito, Y
中科院分区：
文献类型：
--
作者：
Tanaga, K;Bujo, H;Saito, Y
目的：由于某些低密度脂蛋白受体在增厚的内膜中特异性表达，低密度脂蛋白受体亲属（LRs）参与动脉粥样硬化的研究最近得到了新的关注。在这里，我们发现LRP1B是LRs的一个成员，通过增加膜受体、尿激酶型纤溶酶原激活物受体（uPAR）和血小板衍生生长因子受体(PDGFR) β的降解来调节平滑肌细胞（SMCs）的迁移。方法和结果：免疫组化结果显示，LRP1B在人冠状动脉中的表达定位于斑块表面附近的内膜SMCs和内侧SMCs。在培养的SMCs中，LRP1B的表达水平在增殖后期增加。细胞表面和内化实验，结合共免疫沉淀实验，表明LRP1B结合并内化uPAR。代谢标记分析表明，抗lrp1b IgY降低了uPAR的分解代谢。此外，抗lrp1b抗体上调PDGFRbeta蛋白和pdgfr介导的ERK1/2磷酸化水平。最后，抗lrp1b IgY增强了PDGF-BB存在下SMCs的迁移和侵袭。结论- lrp1b可调节uPAR和PDGFR的分解代谢，影响SMCs的迁移。LRP1B的功能特征为阐明动脉粥样硬化斑块中SMC迁移的（病理）生理意义开辟了新的途径。
Objective-Studies on the involvement of low-density lipoprotein receptor relatives (LRs) in atherosclerosis have recently gained new focus because of the specific expression of certain of these receptors in the thickened intima. Here, we show that LRP1B, a member of LRs, modulates the migration of smooth muscle cells (SMCs) by increasing the degradation of membrane receptors, urokinase-type plasminogen activator receptor ( uPAR), and platelet-derived growth factor receptor ( PDGFR) beta.Methods and Results-Immunohistochemistry showed that LRP1B expression in human coronary arteries is localized to the intimal SMCs near the plaque surface as well as to medial SMCs. LRP1B expression levels in cultured SMCs increase at the late phase of proliferation. Cell surface and internalization assays, in combination with coimmunoprecipitation experiments, showed that LRP1B binds and internalizes uPAR. Metabolic labeling analysis demonstrated that anti-LRP1B IgY decreased the catabolism of uPAR. In addition, the anti-LRP1B antibody raised PDGFRbeta protein and PDGFR-mediated phosphorylation levels of ERK1/2. Finally, the anti-LRP1B IgY enhanced the migration and invasion of SMCs in the presence of PDGF-BB.Conclusions-LRP1B modulates the catabolism of uPAR and PDGFR, affecting the migration of SMCs. This functional characterization of LRP1B opens novel avenues for elucidating the (patho) physiological significance of SMC migration in atheromatous plaques.