Modified low density lipoproteins differentially bind and activate the C1 complex of complement
Modified low density lipoproteins differentially bind and activate the C1 complex of complement
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DOI：
10.1016/j.molimm.2006.06.013
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发表时间：
2007-02-01
影响因子：
3.6
通讯作者：
Arlaud, Gerard J.
中科院分区：
文献类型：
--
作者：
Biro, Adrienn;Thielens, Nicole M.;Arlaud, Gerard J.
一些研究表明，补体在动脉粥样硬化形成中起重要作用。为了进一步研究这个问题，我们研究了天然和修饰形式的低密度脂蛋白（LDL）结合和激活C I的能力，C I是触发补体经典途径的复合物。为此目的，LDL是商业获得的，并根据已建立的程序进行纯化，并从每种制剂中产生氧化（oxLDL）和酶促修饰（E-LDL）衍生物。然而，未修饰的LDL和oxLDL样品在过量C1抑制剂存在下不激活C1，通过用蛋白酶然后用胆固醇酯酶顺序处理LDL获得的E-LDL衍生物在这些条件下触发有效的C1激活，在37 ℃下与1 μ M E-LDL孵育90分钟后激活水平接近60%。与这些发现一致，如表面等离子体共振光谱（SPR）所示，C I的C1 q识别亚基显示与未修饰的LDL没有相互作用，但以高亲和力（K-D = 58-75 nM）结合到两种E-LDL样品。更出乎意料的是，尽管它们没有触发直接的C1激活，但两种oxLDL样品也被C1 q有效识别。尽管商业LDL的oxLDL衍生物在C-反应蛋白（CRP）存在下活化C1至显著程度（类似于30%），但使用纯化LDL的oxLDL衍生物获得低得多的活化水平（< 10%）。通过SPR测量，CRP与从纯化的LDL获得的oxLDL和E-LDL衍生物同样良好地结合。这些数据提供了第一个实验证据表明，E-LDL触发有效的C I激活的条件下接近的生理情况下，这表明，激活经典的补体途径，这种衍生物可能是动脉粥样硬化的发病机制中的一个关键因素。相反，oxLDL似乎不太可能在体内直接或以CRP依赖性方式显著激活C1。(c)2006爱思唯尔有限公司保留所有权利。
Several studies suggest that complement plays an important role in atherogenesis. To further investigate this question, we have studied the ability of native and modified forms of low density lipoprotein (LDL) to bind and activate C I, the complex that triggers the classical pathway of complement. For this purpose, LDL was both obtained commercially and purified according to an established procedure, and oxidized (oxLDL) and enzymatically modified (E-LDL) derivatives were generated from each preparation. Whereas the unmodified LDL and oxLDL samples did not activate C I in the presence of excess C1 inhibitor, the E-LDL derivatives obtained by sequential treatment of LDL with a protease and then with cholesterol esterase triggered efficient C I activation under these conditions, with activation levels similar to 60% upon incubation with I mu M E-LDL for 90 min at 37 degrees C. In agreement with these findings, as shown by surface plasmon resonance spectroscopy (SPR), the C1q recognition subunit of C I showed no interaction with unmodified LDL but bound to both E-LDL samples with high affinity (K-D = 58-75 nM). More unexpectedly, although they did not trigger direct C I activation, both oxLDL samples were also efficiently recognized by C1q. Whereas the oxLDL derivative of commercial LDL activated C1 to a significant extent (similar to 30%) in the presence of C-reactive protein (CRP), much lower activation levels (< 10%) were obtained using the oxLDL derivative of purified LDL. As measured by SPR, CRP bound equally well to the oxLDL and E-LDL derivatives obtained from purified LDL. These data provide the first experimental evidence that E-LDL triggers efficient C I activation under conditions close to the physiological situation, suggesting that activation of the classical complement pathway by this derivative may be a crucial factor in the pathogenesis of atherosclerosis. In contrast, it appears unlikely that oxLDL significantly activates C1 directly or in a CRP-dependent manner in vivo. (c) 2006 Elsevier Ltd. All rights reserved.