C-reactive protein-bound enzymatically modified low-density lipoprotein does not transform macrophages into foam cells
C-reactive protein-bound enzymatically modified low-density lipoprotein does not transform macrophages into foam cells
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DOI：
10.4049/jimmunol.180.6.4316
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发表时间：
2008-03-15
影响因子：
4.4
通讯作者：
Agrawal, Alok
中科院分区：
文献类型：
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作者：
Singh, Sanjay K.;Suresh, Madathilparambil V.;Agrawal, Alok
低密度脂蛋白（LDL）胆固醇负载的巨噬细胞泡沫细胞的形成有助于动脉粥样硬化的发展。C-反应蛋白（CRP）与致动脉粥样硬化形式的LDL结合，但CRP在泡沫细胞形成中的作用尚不清楚。在这项研究中，我们首先探讨了CRP的酶修饰LDL（E-LDL），CRP结合的致动脉粥样硬化的LDL模型的结合位点。如前所述，磷酸胆碱（PCh）抑制CRP-E-LDL相互作用，表明CRP的PCh结合位点参与了与E-LDL的结合。然而，CRP中参与CRP-PCh相互作用的氨基酸Phe 66和Glu 81对于CRP-E-LDL相互作用不是必需的。令人惊讶的是，用磷酸乙醇胺（PEt）阻断PCh结合位点显著增加了CRP与E-LDL的结合。PEt介导的CRP与E-LDL结合的增强对E-LDL具有选择性，因为PEt抑制CRP与另一个PCh结合位点-配体肺炎球菌C-多糖的结合。接下来，我们研究了CRP结合的E-LDL的泡沫细胞形成。我们发现，与游离E-LDL不同，CRP结合的E-LDL是无活性的，因为它不会将巨噬细胞转化为泡沫细胞。CRP消除E-LDL活性形成泡沫细胞的功能不受PEt的影响。综合数据，我们得出两个结论。首先，PEt是一种有用的化合物，因为它增强了CRP与E-LDL的结合，因此增加了CRP防止巨噬细胞转化为加载E-LDL的泡沫细胞的效率。第二，CRP阻止泡沫细胞形成的功能可能影响动脉粥样硬化的形成过程。
The formation of low-density lipoprotein (LDL) cholesterol-loaded macrophage foam cells contributes to the development of atherosclerosis. C-reactive protein (CRP) binds to atherogenic forms of LDL, but the role of CRP in foam cell formation is unclear. In this study, we first explored the binding site on CRP for enzymatically modified LDL (E-LDL), a model of atherogenic LDL to which CRP binds. As reported previously, phosphocholine (PCh) inhibited CRP-E-LDL interaction, indicating the involvement of the PCh-binding site of CRP in binding to E-LDL. However, the amino acids Phe66 and Glu81 in CRP that participate in CRP-PCh interaction were not required for CRP-E-LDL interaction. Surprisingly, blocking of the PCh-binding site with phosphoethanolamine (PEt) dramatically increased the binding of CRP to E-LDL. The PEt-mediated enhancement in the binding of CRP to E-LDL was selective for E-LDL because PEt inhibited the binding of CRP to another PCh-binding site-ligand pneumococcal C-polysaccharide. Next, we investigated foam cell formation by CRP-bound E-LDL. We found that, unlike free E-LDL, CRP-bound E-LDL was inactive because it did not transform macrophages into foam cells. The function of CRP in eliminating the activity of E-LDL to form foam cells was not impaired by the presence of PEt. Combined data lead us to two conclusions. First, PEt is a useful compound because it potentiates the binding of CRP to E-LDL and, therefore, increases the efficiency of CRP to prevent transformation of macrophages into E-LDL-loaded foam cells. Second, the function of CRP to prevent formation of foam cells may influence the process of atherogenesis.