激活 CXCR7 可通过增加脂肪组织中的胆固醇摄取来限制动脉粥样硬化并改善高血脂症。
Activation of CXCR7 limits atherosclerosis and improves hyperlipidemia by increasing cholesterol uptake in adipose tissue.
机构信息
Institute for Molecular Cardiovascular Research (X.L., R.R.K., A.T., K.H., S.A., Z.W., M.v.Z., C.W., A.S.), Core Facility Two-Photon Imaging, Interdisciplinary Center for Clinical Research Aachen (S.K.), and Experimental Molecular Imaging (F.G., F.K.), RWTH Aachen University, Aachen, Germany; Institute for Cardiovascular Prevention, Ludwig Maximilians University Munich, Munich, Germany (M.Z., R.R.K., K.H., C.W., A.S.); ChemoCentryx Inc, Mountain View, CA (M.E.P., T.J.S.); Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands (M.v.Z., C.W.); and Munich Heart Alliance, Munich, Germany (C.W., A.S.).
出版信息
Circulation. 2014 Mar 18;129(11):1244-53. doi: 10.1161/CIRCULATIONAHA.113.006840. Epub 2013 Dec 27.
BACKGROUND
The aim of this study was to determine the role of the chemokine receptor CXCR7 in atherosclerosis and vascular remodeling. CXCR7 is the alternative receptor of CXCL12, which regulates stem cell-mediated vascular repair and limits atherosclerosis via its receptor, CXCR4.
METHODS AND RESULTS
Wire-induced injury of the carotid artery was performed in mice with a ubiquitous, conditional deletion of CXCR7 and in mice treated with the synthetic CXCR7 ligand CCX771. The effect of CCX771 treatment on atherosclerosis was studied in apolipoprotein E-deficient (Apoe(-/-)) mice fed a high-fat diet for 12 weeks. Lipoprotein fractions were quantified in the plasma of Apoe(-/-) mice by fast protein liquid chromatography. Uptake of DiI-labeled very low-density lipoprotein to adipose tissue was determined by 2-photon microscopy. We show that genetic deficiency of Cxcr7 increased neointima formation and lesional macrophage accumulation in hyperlipidemic mice after vascular injury. This was related to increased serum cholesterol levels and subsequent hyperlipidemia-induced monocytosis. Conversely, administration of the CXCR7 ligand CCX771 to Apoe(-/-) mice inhibited lesion formation and ameliorated hyperlipidemia after vascular injury and during atherosclerosis. Treatment with CCX771 reduced circulating very low-density lipoprotein levels but not low-density lipoprotein or high-density lipoprotein levels and increased uptake of very low-density lipoprotein into Cxcr7-expressing white adipose tissue. This effect of CCX771 was associated with an enhanced lipase activity and reduced expression of Angptl4 in adipose tissue.
CONCLUSIONS
CXCR7 regulates blood cholesterol by promoting its uptake in adipose tissue. This unexpected cholesterol-lowering effect of CXCR7 is beneficial for atherosclerotic vascular diseases, presumably via amelioration of hyperlipidemia-induced monocytosis, and can be augmented with a synthetic CXCR7 ligand.
背景
本研究旨在探讨趋化因子受体 CXCR7 在动脉粥样硬化和血管重构中的作用。CXCR7 是 CXCL12 的替代受体，通过其受体 CXCR4 调节干细胞介导的血管修复，并限制动脉粥样硬化的发生。
方法和结果
在具有普遍条件性 CXCR7 缺失的小鼠和接受合成 CXCR7 配体 CCX771 治疗的小鼠中，进行颈动脉线诱导损伤。在高脂饮食喂养 12 周的载脂蛋白 E 缺陷（Apoe(-/-)）小鼠中研究 CCX771 治疗对动脉粥样硬化的影响。通过快速蛋白液相色谱法定量测定 Apoe(-/-)小鼠血浆中的脂蛋白分数。通过双光子显微镜测定 DiI 标记的极低密度脂蛋白向脂肪组织的摄取。我们发现，在高脂血症小鼠血管损伤后，Cxcr7 的基因缺失增加了新生内膜形成和病变部位巨噬细胞的积累。这与血清胆固醇水平升高以及随后的高脂血症诱导单核细胞增多有关。相反，在血管损伤后和动脉粥样硬化期间，给予 Apoe(-/-)小鼠 CXCR7 配体 CCX771 可抑制病变形成并改善高脂血症。CCX771 的治疗降低了循环极低密度脂蛋白水平，但不降低低密度脂蛋白或高密度脂蛋白水平，并增加了 Cxcr7 表达的白色脂肪组织对极低密度脂蛋白的摄取。CCX771 的这种作用与脂肪组织中脂肪酶活性的增强和 Angptl4 表达的降低有关。
结论
CXCR7 通过促进其在脂肪组织中的摄取来调节血液胆固醇。CXCR7 的这种出乎意料的降胆固醇作用对动脉粥样硬化性血管疾病有益，可能是通过改善高脂血症诱导的单核细胞增多症，并且可以通过合成 CXCR7 配体增强。
Zotero 插件