Center for Preventive Cardiology, Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR (P.A.M., H.T., K.H., I.G., S.F.).
Division of Cardiovascular Medicine (L.Z., M.F.L.).
Circulation. 2018 Oct 23;138(17):1850-1863. doi: 10.1161/CIRCULATIONAHA.117.031702.
We previously showed that mice lacking MΦLRP1 (low-density lipoprotein receptor-related protein 1 in macrophages) undergo accelerated atherosclerotic plaque formation due to changes in macrophages including increased apoptosis, decreased efferocytosis, and exaggerated transition to the inflammatory M1 phenotype. Here we sought to explore the role of macrophage low-density lipoprotein receptor-related protein 1 during regression of atherosclerosis since regressing plaques are characterized by transitioning of macrophages to M2 status as inflammation resolves.
Apolipoprotein E mice on a high-fat diet for 12 weeks were reconstituted with bone marrow from apolipoprotein E-producing wild-type or MΦLRP1 mice, and then placed on a chow diet for 10 weeks (n=9 to 11 mice/group). A cohort of apolipoprotein E mice reconstituted with apolipoprotein E bone marrow served as baseline controls (n=9).
Plaques of both wild-type and MΦLRP1 bone marrow recipients regressed compared with controls (11% and 22%, respectively; P<0.05), and plaques of MΦLRP1 recipients were 13% smaller than those of wild-type recipients ( P<0.05). Recipients of MΦLRP1 marrow had 36% fewer M1 macrophages ( P<0.01) and 2.5-fold more CCR7 (C-C chemokine receptor type 7)-positive macrophages in the plaque relative to wild-type mice ( P<0.01). Additionally, in vivo studies of cellular egress showed a 4.6-fold increase in 5-ethynyl-2´-deoxyuridine-labeled CCR7 macrophages in mediastinal lymph nodes. Finally, in vivo studies of reverse cholesterol transport showed a 1.4-fold higher reverse cholesterol transport in MΦLRP1 recipient mice ( P<0.01).
Absence of macrophage low-density lipoprotein receptor-related protein 1 unexpectedly accelerates atherosclerosis regression, enhances reverse cholesterol transport, and increases expression of the motility receptor CCR7, which drives macrophage egress from lesions.
我们之前的研究表明，由于巨噬细胞发生变化，包括凋亡增加、吞噬作用减少和向炎症 M1 表型的过度转化，缺乏 MΦLRP1（巨噬细胞中的低密度脂蛋白受体相关蛋白 1）的小鼠会加速动脉粥样硬化斑块的形成。在这里，我们试图探索巨噬细胞低密度脂蛋白受体相关蛋白 1 在动脉粥样硬化消退过程中的作用，因为消退的斑块的特征是随着炎症的消退，巨噬细胞向 M2 状态转化。
用高脂饮食喂养 12 周的载脂蛋白 E 小鼠用产生载脂蛋白 E 的野生型或 MΦLRP1 骨髓细胞重建，然后用普通饮食喂养 10 周（每组 9 到 11 只小鼠）。一组用载脂蛋白 E 骨髓细胞重建的载脂蛋白 E 小鼠作为基线对照（n=9）。
与对照组相比，野生型和 MΦLRP1 骨髓细胞受者的斑块均发生了消退（分别为 11%和 22%；P<0.05），且 MΦLRP1 受者的斑块比野生型受者小 13%（P<0.05）。MΦLRP1 骨髓细胞受者斑块中 M1 巨噬细胞减少 36%（P<0.01），CCR7（C-C 趋化因子受体 7）阳性巨噬细胞增加 2.5 倍（P<0.01）。此外，体内细胞迁出研究显示，在胸内淋巴结中，5-乙炔基-2´-脱氧尿苷标记的 CCR7 巨噬细胞增加了 4.6 倍。最后，体内胆固醇逆向转运研究显示，MΦLRP1 受者的胆固醇逆向转运增加了 1.4 倍（P<0.01）。
出乎意料的是，巨噬细胞低密度脂蛋白受体相关蛋白 1 的缺失加速了动脉粥样硬化的消退，增强了胆固醇的逆向转运，并增加了运动受体 CCR7 的表达，从而驱动巨噬细胞从病变中迁出。
