Department of Biomedical Sciences, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States.
Front Immunol. 2020 Aug 11;11:1780. doi: 10.3389/fimmu.2020.01780. eCollection 2020.
The aim of this study was to test the hypothesis that C-reactive protein (CRP) protects against the development of atherosclerosis and that a conformational alteration of wild-type CRP is necessary for CRP to do so. Atherosclerosis is an inflammatory cardiovascular disease and CRP is a plasma protein produced by the liver in inflammatory states. The co-localization of CRP and low-density lipoproteins (LDL) at atherosclerotic lesions suggests a possible role of CRP in atherosclerosis. CRP binds to phosphocholine-containing molecules but does not interact with LDL unless the phosphocholine groups in LDL are exposed. However, CRP can bind to LDL, without the exposure of phosphocholine groups, if the native conformation of CRP is altered. Previously, we reported a CRP mutant, F66A/T76Y/E81A, generated by site-directed mutagenesis, that did not bind to phosphocholine. Unexpectedly, this mutant CRP, without any more conformational alteration, was found to bind to atherogenic LDL. We hypothesized that this CRP mutant, unlike wild-type CRP, could be anti-atherosclerotic and, accordingly, the effects of mutant CRP on atherosclerosis in atherosclerosis-prone LDL receptor-deficient mice were evaluated. Administration of mutant CRP into mice every other day for a few weeks slowed the progression of atherosclerosis. The size of atherosclerotic lesions in the aorta of mice treated with mutant CRP for 9 weeks was ~40% smaller than the lesions in the aorta of untreated mice. Thus, mutant CRP conferred protection against atherosclerosis, providing a proof of concept that a local inflammation-induced structural change in wild-type CRP is a prerequisite for CRP to control the development of atherosclerosis.
这项研究的目的是验证以下假设，即 C 反应蛋白（CRP）可以预防动脉粥样硬化的发生，并且 CRP 的野生型构象改变是 CRP 发挥此作用的必要条件。动脉粥样硬化是一种炎症性心血管疾病，CRP 是肝脏在炎症状态下产生的一种血浆蛋白。CRP 与 LDL 在动脉粥样硬化病变中的共定位提示 CRP 可能在动脉粥样硬化中发挥作用。CRP 与含有磷酸胆碱的分子结合，但除非 LDL 中的磷酸胆碱基团暴露，否则不会与 LDL 相互作用。然而，如果 CRP 的天然构象发生改变，CRP 可以在不暴露磷酸胆碱基团的情况下与 LDL 结合。此前，我们报道了一种通过定点突变产生的 CRP 突变体 F66A/T76Y/E81A，该突变体不与磷酸胆碱结合。出乎意料的是，这种 CRP 突变体，在没有更多构象改变的情况下，被发现与致动脉粥样硬化的 LDL 结合。我们假设，这种 CRP 突变体与野生型 CRP 不同，可能具有抗动脉粥样硬化作用，因此评估了突变型 CRP 对动脉粥样硬化易感 LDL 受体缺陷小鼠动脉粥样硬化的影响。每隔一天向小鼠体内注射突变型 CRP 数周可减缓动脉粥样硬化的进展。用突变型 CRP 处理 9 周的小鼠主动脉中的动脉粥样硬化病变的大小比未经处理的小鼠主动脉中的病变小约 40%。因此，突变型 CRP 提供了针对动脉粥样硬化的保护作用，为 CRP 控制动脉粥样硬化发展的局部炎症诱导的野生型 CRP 结构改变是其先决条件这一概念提供了证据。
