Pharmacological Inhibition of the Chemokine Receptor, CX3CR1, Reduces Atherosclerosis in Mice
Pharmacological Inhibition of the Chemokine Receptor, CX3CR1, Reduces Atherosclerosis in Mice
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DOI：
10.1161/atvbaha.112.300930
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发表时间：
2013-10-01
影响因子：
8.7
通讯作者：
Combadiere, Christophe
中科院分区：
文献类型：
--
作者：
Poupel, Lucie;Boissonnas, Alexandre;Combadiere, Christophe
目的研究趋化因子受体CX 3CR 1基因的改变与人心肌梗死和小鼠动脉粥样硬化的发生有关。在这项研究中，我们解决了CX 3CR 1拮抗剂是否是潜在的治疗工具，以限制急性和慢性炎症过程中atherosclerosis.Approach和结果治疗与F1，一个氨基末端修饰的CX 3CR 1配体赋予CX 3CR 1拮抗剂活性，减少了动脉粥样硬化病变的程度在Apoe（-/-）和Ldlr（-/-）proatherogenic小鼠模型。在F1处理的Apoe（-/-）小鼠中，主动脉窦中的巨噬细胞蓄积减少，但在F1处理的小鼠和对照小鼠中，病变的巨噬细胞密度相似。体外和体内F1治疗均降低CX 3CR 1依赖性炎症单核细胞粘附，可能限制其募集。此外，F1处理的Apoe（-/-）小鼠显示血液炎性单核细胞数量减少，而常驻单核细胞数量保持不变。体外和体内F1处理均降低CX 3CR 1依赖性炎性单核细胞存活。最后，F1治疗Apoe（-/-）小鼠与先进的动脉粥样硬化导致较小的病变比未经处理的小鼠，但没有恢复到最初的phenotype.Conclusions的CX 3CR 1拮抗剂F1是一个有效的抑制剂动脉粥样硬化病变的进展，通过其选择性影响炎症单核细胞功能。控制单核细胞的运输和存活可能是传统用于治疗动脉粥样硬化的降脂药物的替代或补充疗法。
Objective Alterations of the chemokine receptor CX3CR1 gene were associated with a reduced risk of myocardial infarction in human and limited atherosclerosis in mice. In this study, we addressed whether CX3CR1 antagonists are potential therapeutic tools to limit acute and chronic inflammatory processes in atherosclerosis.Approach and Results Treatment with F1, an amino terminus-modified CX3CR1 ligand endowed with CX3CR1 antagonist activity, reduced the extent of atherosclerotic lesions in both Apoe(-/-) and Ldlr(-/-) proatherogenic mouse models. Macrophage accumulation in the aortic sinus was reduced in F1-treated Apoe(-/-) mice but the macrophage density of the lesions was similar in F1-treated and control mice. Both in vitro and in vivo F1 treatment reduced CX3CR1-dependent inflammatory monocyte adhesion, potentially limiting their recruitment. In addition, F1-treated Apoe(-/-) mice displayed reduced numbers of blood inflammatory monocytes, whereas resident monocyte numbers remained unchanged. Both in vitro and in vivo F1 treatment reduced CX3CR1-dependent inflammatory monocyte survival. Finally, F1 treatment of Apoe(-/-) mice with advanced atherosclerosis led to smaller lesions than untreated mice but without reverting to the initial phenotype.Conclusions The CX3CR1 antagonist F1 is a potent inhibitor of the progression of atherosclerotic lesions by means of its selective impact on inflammatory monocyte functions. Controlling monocyte trafficking and survival may be an alternative or complementary therapy to lipid-lowering drugs classically used in the treatment of atherosclerosis.