Complement and atherogenesis - Binding of CRP to degraded, nonoxidized LDL enhances complement activation
Complement and atherogenesis - Binding of CRP to degraded, nonoxidized LDL enhances complement activation
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DOI：
10.1161/01.atv.19.10.2348
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发表时间：
1999-10-01
影响因子：
8.7
通讯作者：
Hemmes, M
中科院分区：
文献类型：
--
作者：
Bhakdi, S;Torzewski, M;Hemmes, M
在动脉粥样硬化早期，补体激活与低密度脂蛋白（LDL）在内皮下的沉积在时间上相关，并且补体在促进病变进展中也起致病作用。已确定两种可能导致补体激活的病变成分。首先，LDL的酶促降解产生一种可自发激活补体的衍生物，并且在病变中已检测到酶促降解的LDL（E - LDL）。其次，C - 反应蛋白（CRP）与补体C5b - 9共定位，这通过对早期动脉粥样硬化病变的免疫组织学研究得以证明，所以这种急性期蛋白也具有激活补体功能的可能性是存在的。在此，我们报道向人血清中添加LDL和CRP不会导致显著的C3转换。添加E - LDL会引发补体激活，而CRP可显著增强这种激活。蔗糖浮选实验证明了CRP与E - LDL的结合。这种结合依赖于Ca²⁺，并且可被磷酸胆碱抑制，用磷脂酶C处理可破坏E - LDL的补体激活特性。这些结果表明，CRP与在酶促降解的LDL颗粒中暴露出来的磷酸胆碱基团结合。免疫组织学研究补充了这些发现，表明在人类早期动脉粥样硬化病变中CRP与E - LDL共定位。因此，组织沉积的LDL的酶促非氧化修饰有望赋予该分子结合CRP的能力。——随之而来的补体激活增强可能与动脉粥样硬化病变的发生和发展有关。
Complement activation occurs in temporal correlation with the subendothelial deposition of LDL during early atherogenesis, and complement also plays a pathogenetic role in promoting lesion progression. Two lesion components have been identified that may be responsible for complement: activation. First, enzymatic degradation of LDL generates a derivative that can spontaneously activate complement, and enzymatically degraded LDL (E-LDL) has been detected in the lesions. Second, C-reactive protein (CRP) colocalizes with complement C5b-9, as evidenced by immunohistological studies of early atherosclerotic lesions, so the possibility exists that this acute phase protein also fulfills a complement-activating function. Here, we report that addition of LDL and CRP to human serum did not result in significant C3 turnover. Addition of E-LDL provoked complement activation, which was markedly enhanced by CRP, Binding of CRP to E-LDL was demonstrated by sucrose flotation experiments. Binding was Ca2+-dependent and inhibitable by phosphorylcholine, and the complement-activating property of E-LDL was destroyed by treatment with phospholipase C. These results indicated that CRP binds to phosphorylcholine groups that become exposed in enzymatically degraded LDL particles. Immunohistological studies complemented these findings in showing that CRP colocalizes with E-LDL in early human atherosclerotic lesions. Thus enzymatic, nonoxidative modification of tissue-deposited LDL can be expected to confer CRP-binding capacity onto the molecule.-The ensuing enhancement of complement activation may be relevant to the development and progression of the atherosclerotic lesion.