Tanaga Kousei, Bujo Hideaki, Zhu Yanjuan, Kanaki Tatsuro, Hirayama Satoshi, Takahashi Kazuo, Inoue Masahiro, Mikami Keiji, Schneider Wolfgang J, Saito Yasushi
Department of Clinical Cell Biology, Chiba University Graduate School of Medicine, Chiba, Japan.
Arterioscler Thromb Vasc Biol. 2004 Aug;24(8):1422-8. doi: 10.1161/01.ATV.0000133607.80554.09. Epub 2004 May 27.
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.
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.
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.
由于某些低密度脂蛋白受体相关蛋白（LRs）在增厚的内膜中特异性表达，近年来关于其在动脉粥样硬化中的作用研究有了新的焦点。在此，我们表明LRs成员之一的LRP1B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（SMC）的迁移。
免疫组织化学显示，LRP1B在人冠状动脉中的表达定位于斑块表面附近的内膜SMC以及中膜SMC。培养的SMC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免疫共沉淀实验表明，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抗体提高了PDGFRβ蛋白水平以及PDGFR介导的ERK1/2磷酸化水平。最后，在存在血小板衍生生长因子BB（PDGF - BB）的情况下，抗LRP1B IgY增强了SMC的迁移和侵袭。
LRP1B调节uPAR和PDGFR的分解代谢，影响SMC的迁移。LRP1B的这一功能特性为阐明SMC迁移在动脉粥样硬化斑块中的（病理）生理意义开辟了新途径。
