Decreased atherosclerotic lesion formation in CX3CR1/apolipoprotein E double knockout mice
Decreased atherosclerotic lesion formation in CX3CR1/apolipoprotein E double knockout mice
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DOI：
10.1161/01.cir.0000057548.68243.42
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发表时间：
2003-02-25
期刊：
影响因子：
37.8
通讯作者：
Mallat, Z
中科院分区：
文献类型：
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作者：
Combadière, C;Potteaux, S;Mallat, Z
背景-Fractalkine（CX3CL1）是一种CX3C趋化因子，表达于血管壁，介导表达其受体CX3CR1的白细胞的牢固粘附和趋化。CX3CR1基因的多态性与CX3CR1低表达和降低人类急性冠状动脉疾病的风险有关。方法和结果-我们通过靶向基因破坏产生CX3CR1缺陷小鼠（CX3CR1（-/-）），并将其与致动脉粥样硬化的载脂蛋白E缺陷小鼠（apoE（-/-））杂交。在这里，我们发现，与同窝出生的CX3CR1（+/+）/apoE（-/-）小鼠相比，CX3CR1/apoE双基因敲除小鼠胸主动脉脂质染色病变的程度减少了59%。在双基因敲除小鼠中，主动脉窦中动脉粥样硬化的发展也显著改变，巨噬细胞积聚减少50%。尽管CX3CR1（-/-）小鼠的病变尺寸较小，但它们保留了大量平滑肌细胞和胶原蛋白的积累，这些特征与稳定的斑块表型一致。最后，CX3CR1（+/-）/apoE（-/-）小鼠显示出与CX3CR1（-/-）/apoE（-/-）小鼠相同的动脉粥样硬化的减少。
Background-Fractalkine (CX3CL1), a CX3C chemokine, is expressed in the vessel wall and mediates the firm adhesion and chemotaxis of leukocytes expressing its receptor, CX3CR1. A polymorphism in the CX3CR1 gene is associated with low CX3CR1 expression and reduced risk of acute coronary disease in humans.Methods and Results-We generated CX3CR1-deficient mice (CX3CR1(-/-)) by targeted gene disruption and crossed them with the proatherogenic apolipoprotein E-deficient mice (apoE(-/-)). Here we show that the extent of lipid-stained lesions in the thoracic aorta was reduced by 59% in CX3CR1/apoE double knockout mice compared with their CX3CR1(+/+)/apoE(-/-) littermates. The development of atherosclerosis in the aortic sinus was also markedly altered in the double knockout mice, with 50% reduction in macrophage accumulation. Although lesions of CX3CR1(-/-) mice were smaller in size, they retained a substantial accumulation of smooth muscle cells and collagen, features consistent with a stable plaque phenotype. Finally, CX3CR1(+/-) /apoE(-/-)mice showed the same reduction in atherosclerosis as the CX3CR1(-/-)/apoE(-/-) mice.Conclusions-The CX3CR1-CX3CL1 pathway seems to play a direct and critical role in monocyte recruitment and atherosclerotic lesion development in a mouse model of human atherosclerosis.