Activation of CXCR7 Limits Atherosclerosis and Improves Hyperlipidemia by Increasing Cholesterol Uptake in Adipose Tissue
Activation of CXCR7 Limits Atherosclerosis and Improves Hyperlipidemia by Increasing Cholesterol Uptake in Adipose Tissue
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DOI：
10.1161/circulationaha.113.006840
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发表时间：
2014-03-18
期刊：
影响因子：
37.8
通讯作者：
Schober, Andreas
中科院分区：
文献类型：
--
作者：
Li, Xiaofeng;Zhu, Mengyu;Schober, Andreas
本研究的目的是确定趋化因子受体CXCR 7在动脉粥样硬化和血管重塑中的作用。CXCR 7是CXCL 12的替代受体，CXCL 12通过其受体CXCR 4调节干细胞介导的血管修复并限制动脉粥样硬化。方法和结果在CXCR 7普遍存在的条件性缺失的小鼠和用合成的CXCR 7配体CCX 771治疗的小鼠中进行线诱导的颈动脉损伤。在高脂饮食喂养12周的载脂蛋白E缺陷（Apoe（-/-））小鼠中研究了CCX 771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Apoe（-/-）小鼠血浆中的脂蛋白组分。用双光子显微镜测定脂肪组织对DiI标记极低密度脂蛋白的摄取。我们表明，Cxcr 7的遗传缺陷增加了血管损伤后高脂血症小鼠的新生内膜形成和病变巨噬细胞积聚。这与血清胆固醇水平升高和随后的高脂血症诱导的单核细胞增多症有关。相反，给予Apoe（-/-）小鼠CXCR 7配体CCX 771可抑制血管损伤后和动脉粥样硬化期间的病变形成并改善高脂血症。CCX 771治疗降低了循环极低密度脂蛋白水平，但未降低低密度脂蛋白或高密度脂蛋白水平，并增加了表达Cxcr 7的白色脂肪组织对极低密度脂蛋白的摄取。CCX 771的这种作用与脂肪酶活性增强和脂肪组织中Angptl 4表达减少有关。结论CXCR 7通过促进脂肪组织对胆固醇的摄取来调节血胆固醇。CXCR 7的这种意想不到的降低胆固醇的作用对于动脉粥样硬化性血管疾病是有益的，可能是通过改善高血压诱导的单核细胞增多，并且可以用合成的CXCR 7配体增强。
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.