C-reactive protein-mediated vascular injury requires complement.
C-reactive protein-mediated vascular injury requires complement.
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DOI：
10.1161/atvbaha.110.205377
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发表时间：
2010-06
期刊：
影响因子：
--
通讯作者：
Szalai AJ
中科院分区：
文献类型：
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作者：
Hage FG;Oparil S;Xing D;Chen YF;McCrory MA;Szalai AJ
我们之前已经证明，与非转基因（NTG）小鼠相比，人类c反应蛋白转基因（CRPtg）小鼠血管损伤诱导的新生内膜形成被夸大。我们现在检验这个假设，即补体对这种效果是必需的。具有正常补体系统的CRPtg和NTG与缺乏补体蛋白C3表达的对应体（CRPtg/C3-/-和NTG/C3-/-）进行颈动脉结扎。28天后，与NTG相比，CRPtg损伤血管的新生内膜更厚，周围外膜的免疫反应性C3更多。与NTG或NTG/C3-/-相比，CRPtg/C3-/-组新生内膜厚度没有增加。降低人CRP血液水平（通过给予选择性反义寡核苷酸）消除了与血管损伤相关的血清C3的消耗，并减少了由此产生的病变中的免疫反应性C3。在与F4/80（巨噬细胞标志物）共定位的损伤血管中以及体外，人CRP诱导骨髓源性巨噬细胞增加C3的表达。损伤小鼠颈动脉中新内膜形成的人CRP升高与循环C3减少和组织局部C3增加有关。C3消除或人体CRP的药理学减少可防止CRP驱动的损伤反应加剧。在CRPtg模型系统中，小鼠C3对人CRP的作用至关重要。
We previously demonstrated that vascular injury-induced neointima formation is exaggerated in human C-reactive protein transgenic (CRPtg) compared to non-transgenic (NTG) mice. We now test the hypothesis that complement is required for this effect. CRPtg and NTG with a normal complement system versus their counterparts lacking expression of complement protein C3 (CRPtg/C3-/- and NTG/C3-/-) underwent carotid artery ligation. 28 days later, the injured vessels in CRPtg had thicker neointimas and more immunoreactive C3 in the surrounding adventitia compared to NTG. In CRPtg/C3-/- there was no increase in neointimal thickness compared to NTG or NTG/C3-/-. Decreasing human CRP blood levels (via administration of a selective antisense oligonucleotide) eliminated the depletion of serum C3 associated with vascular injury and reduced immunoreactive C3 in the resultant lesions. In injured vessels C3 co-localized with F4/80 (macrophage marker) and in-vitro, human CRP elicited increased expression of C3 by bone-marrow derived macrophages. Human CRP exaggeration of neointima formation in injured mouse carotid arteries associates with decreased circulating C3 and increased tissue-localized C3. C3 elimination or pharmacological reduction of human CRP prevents CRP-driven exacerbation of the injury response. In the CRPtg model system, mouse C3 is essential for the effect of human CRP.