Boring L, Gosling J, Cleary M, Charo I F
Gladstone Institute of Cardiovascular Disease, San Francisco, California 94141, USA.
Nature. 1998 Aug 27;394(6696):894-7. doi: 10.1038/29788.
Chemokines are proinflammatory cytokines that function in leukocyte chemoattraction and activation and have recently been shown to block the HIV-1 infection of target cells through interactions with chemokine receptors. In addition to their function in viral disease, chemokines have been implicated in the pathogenesis of atherosclerosis. Expression of the CC chemokine monocyte chemoattractant protein-1 (MCP-1) is upregulated in human atherosclerotic plaques, in arteries of primates on a hypercholesterolaemic diet; and in vascular endothelial and smooth muscle cells exposed to minimally modified lipids. To determine whether MCP-1 is causally related to the development of atherosclerosis, we generated mice that lack CCR2, the receptor for MCP-1 (ref. 7), and crossed them with apolipoprotein (apo) E-null mice which develop severe atherosclerosis. Here we show that the selective absence of CCR2 decreases lesion formation markedly in apoE-/- mice but has no effect on plasma lipid or lipoprotein concentrations. These data reveal a role for MCP-1 in the development of early atherosclerotic lesions and suggest that upregulation of this chemokine by minimally oxidized lipids is an important link between hyperlipidaemia and fatty streak formation.
趋化因子是一类促炎细胞因子，在白细胞趋化和激活过程中发挥作用，最近研究表明，趋化因子可通过与趋化因子受体相互作用来阻断靶细胞的HIV-1感染。除了在病毒性疾病中发挥作用外，趋化因子还与动脉粥样硬化的发病机制有关。CC趋化因子单核细胞趋化蛋白-1（MCP-1）在人类动脉粥样硬化斑块、高胆固醇饮食的灵长类动物动脉以及暴露于轻度修饰脂质的血管内皮和平滑肌细胞中表达上调。为了确定MCP-1是否与动脉粥样硬化的发展存在因果关系，我们培育出了缺乏MCP-1受体CCR2的小鼠（参考文献7），并将它们与会发生严重动脉粥样硬化的载脂蛋白E基因敲除小鼠进行杂交。在此我们表明，CCR2的选择性缺失显著减少了载脂蛋白E基因敲除小鼠的损伤形成，但对血浆脂质或脂蛋白浓度没有影响。这些数据揭示了MCP-1在早期动脉粥样硬化病变发展中的作用，并表明轻度氧化脂质对这种趋化因子的上调是高脂血症与脂肪条纹形成之间的重要联系。
