Transgenic human C-reactive protein is not proatherogenic in apolipoprotein E-deficient mice
Transgenic human C-reactive protein is not proatherogenic in apolipoprotein E-deficient mice
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DOI：
10.1073/pnas.0503202102
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发表时间：
2005-06-07
影响因子：
11.1
通讯作者：
Pepys, MB
中科院分区：
文献类型：
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作者：
Hirschfield, GM;Gallimore, JR;Pepys, MB
循环中C反应蛋白(CRP)浓度与未来动脉粥样硬化血栓形成事件之间的关联已引起人们对CRP可能的致病作用的猜测。然而，我们在这里表明，尽管人CRP和小鼠补体成分3在斑块中沉积，但转基因表达的人CRP对雄性载脂蛋白E(ApoE)缺陷C57BL/6小鼠的发展、进展或自发性动脉粥样硬化的严重程度或发病率或死亡率没有影响，直到56周。尽管女性载脂蛋白E基因敲除基因比男性更容易发生动脉粥样硬化，但人类的CRP转基因受性激素控制，并且只在男性的人类水平上表达。因此，我们只研究了雄性小鼠。小鼠血清Anyloid P组分的浓度始终保持正常，这是一个极其敏感的系统性炎症标志物，除了少数动物对打斗的短暂尖峰反应外，这表明在该模型中，动脉粥样硬化的形成与急性时相反应无关。然而，在人类CRP转基因小鼠中，apoE基因敲除小鼠的循环CRP浓度高于野生型对照小鼠。在apoE缺乏的动物中，较高的CRP值与显著较低的雌二醇浓度相关。因此，人CRP转基因表达在apoE缺陷小鼠中上调，显然反映了雌激素水平的变化，尽管没有其他全身炎症的迹象。必须警惕人类C反应蛋白与载脂蛋白E缺乏介导的小鼠动脉粥样硬化的异种组合对人类病理学的推断。然而，目前的结果并不表明人的CRP在体内既不是致动脉粥样硬化的，也不是具有动脉粥样硬化保护作用的。
The association between circulating concentrations of C-reactive protein (CRP) and future atherothrombotic events has provoked speculation about a possible pathogenetic role of CRP. However, we show here that transgenic expression of human CRP had no effect on development, progression, or severity of spontaneous atherosclerosis, or on morbidity or mortality, in male apolipoprotein E (apoE)-deficient C57BL/6 mice up to 56 weeks, despite deposition of human CRP and mouse complement component 3 in the plaques. Although female apoE knockouts develop atherosclerosis more rapidly than males, the human CRP transgene is under sex hormone control and is expressed at human levels only in males. We therefore studied only male mice. The concentration of mouse serum annyloid P component, an extremely sensitive systemic marker of inflammation, remained normal throughout except for transient spikes in response to fighting in a few animals, indicating that atherogenesis in this model is not associated with an acute-phase response. However, among human CRP transgenic mice, the circulating CRP concentration was higher in apoE knockouts than in wild-type controls. The higher CRP values were associated with substantially lower estradiol concentrations in the apoE-deficient animals. Human CRP transgene expression is thus up-regulated in apoE-deficient mice, apparently reflecting altered estrogen levels, despite the absence of other systemic signs of inflammation. Extrapolation to human pathology from this xenogeneic combination of human CRP with apoE deficiency-mediated mouse atherosclerosis must be guarded. Nevertheless, the present results do not suggest that human CRP is either proatherogenic or atheroprotective in vivo.