Schwedler Susanne B, Amann Kerstin, Wernicke Konstanze, Krebs Alexander, Nauck Matthias, Wanner Christoph, Potempa Lawrence A, Galle Jan
Division of Nephrology, Department of Medicine, University of Würzburg, Würzburg, Germany.
Circulation. 2005 Aug 16;112(7):1016-23. doi: 10.1161/CIRCULATIONAHA.105.556530. Epub 2005 Aug 8.
C-reactive protein (CRP) may have proatherogenic but also vasoprotective properties. We tested the hypothesis that the configuration of CRP (pentameric, or native [nCRP], versus monomeric, or modified [mCRP]) determines these different characteristics in an in vivo model.
We investigated the effects of human nCRP and mCRP on the development of atherosclerosis in apolipoprotein E-knockout (ApoE(-/-)) mice. Treatment with nCRP for 8 weeks (2.5 mg/kg SC weekly) resulted in a 4-fold-higher mean aortic plaque area in 14-week-old female ApoE(-/-) mice compared with the saline controls. In contrast, mean plaque size was decreased by approximately 50% in mCRP-treated ApoE(-/-) mice (2.5 mg/kg SC weekly). Using immunohistochemistry, we report the natural presence of the mCRP antigen in saline controls. mCRP antigen was expressed in smooth muscle cells and extracellularly in the vicinity of the plaques to a similar level in both CRP-treated groups and saline controls. mCRP and ApoB colocalized with macrophages and were equally upregulated in all aortic plaques. Vascular cell adhesion molecule expression was increased, and CD154 and intercellular adhesion molecule showed a trend for higher expression in nCRP-treated compared with mCRP-treated mice. CD154 expression in the vessel wall and plaque size correlated significantly. mCRP-treated ApoE(-/-) exhibited higher serum levels of the antiinflammatory interleukin-10 compared with the other 2 groups.
Here, we show that mCRP and nCRP have opposite effects on atherosclerosis in ApoE(-/-) mice. These data may explain in part the conflicting activities previously reported for CRP in models of atherogenesis.
C反应蛋白（CRP）可能具有促动脉粥样硬化特性，但也有血管保护特性。我们在体内模型中验证了CRP的构型（五聚体，即天然型[nCRP]，与单体，即修饰型[mCRP]）决定这些不同特性的假说。
我们研究了人nCRP和mCRP对载脂蛋白E基因敲除（ApoE(-/-)）小鼠动脉粥样硬化发展的影响。14周龄雌性ApoE(-/-)小鼠经nCRP治疗8周（每周皮下注射2.5 mg/kg），与生理盐水对照组相比，平均主动脉斑块面积增大了4倍。相比之下，mCRP治疗的ApoE(-/-)小鼠（每周皮下注射2.5 mg/kg）平均斑块大小减少了约50%。通过免疫组织化学，我们发现生理盐水对照组中天然存在mCRP抗原。mCRP抗原在平滑肌细胞中表达，并在斑块附近细胞外表达，在CRP治疗组和生理盐水对照组中水平相似。mCRP和载脂蛋白B与巨噬细胞共定位，且在所有主动脉斑块中均同等上调。血管细胞黏附分子表达增加，与mCRP治疗的小鼠相比，nCRP治疗的小鼠中CD154和细胞间黏附分子有表达升高的趋势。血管壁中CD154表达与斑块大小显著相关。与其他两组相比，mCRP治疗的ApoE(-/-)小鼠血清中抗炎性白细胞介素-10水平更高。
在此，我们表明mCRP和nCRP对ApoE(-/-)小鼠的动脉粥样硬化有相反作用。这些数据可能部分解释了先前在动脉粥样硬化模型中报道的CRP的矛盾活性。
