Human C-reactive protein slows atherosclerosis development in a mouse model with human-like hypercholesterolemia
Human C-reactive protein slows atherosclerosis development in a mouse model with human-like hypercholesterolemia
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DOI：
10.1073/pnas.0706027104
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发表时间：
2007-08-21
影响因子：
11.1
通讯作者：
Bjorkegren, Johan
中科院分区：
文献类型：
--
作者：
Kovacs, Alexander;Tornvall, Per;Bjorkegren, Johan
急性期反应物C-反应蛋白（CRP）的基线值的增加与未来的心血管疾病显著相关，并且一些体外研究已经声称人CRP（hCRP）具有促动脉粥样硬化作用。然而，在载脂蛋白E基因缺陷小鼠模型中的体内研究给出了相互矛盾的结果。我们饲养了具有动脉粥样硬化倾向的小鼠（Apob（100/100）Ldlr（-1-））和hCRP转基因小鼠（hCRP（+/0）），并研究了15、30、40和50周龄时的病变发展。hCRP（+/0）Apob（100/100）Ldlr（-1-）小鼠的动脉粥样硬化病变小于hCRP（+/0）Apob（100/100）Ldlr（-1-）对照小鼠，根据40周龄和50周龄小鼠的固定动脉瘤病变表面积判断。在40周龄小鼠的病变中，hCRP（+/0）Apob（100/100）Ldlr（-1-）小鼠中蛋白酶体降解途径中几个基因的mRNA表达水平高于同窝对照小鼠，如整体基因表达谱所示。这些结果通过实时PCR得到证实，这也表明hCRP（+/0）Apob（100/100）Ldlr（-1-）小鼠中这些基因的活性在30周和40周时相同，但在40周时显著低于对照组的30周。我们的研究结果表明，hCRP不是促动脉粥样硬化，而是减缓动脉粥样硬化的形成，可能是通过蛋白酶体介导的蛋白质降解。
increased baseline values of the acute-phase reactant C-reactive protein (CRP) are significantly associated with future cardiovascular disease, and some in vitro studies have claimed that human CRP (hCRP) has proatherogenic effects. In vivo studies in apolipoprotein E-cleficient mouse models, however, have given conflicting results. We bred atherosclerosis-prone mice (Apob(100/100)Ldlr(-1-)), which have human-like hypercholesterolemia, with hCRP transgenic mice (hCRP(+/0)) and studied lesion development at 15, 30, 40, and 50 weeks of age. Atherosclerotic lesions were smaller in hCRP(+/0) Apob(100/100)Ldlr(-1-) mice than in hCRP(+/0)Apob(100/100)Ldlr(-1-) controls, as judged from the lesion surface areas of pinned-out aortas from mice at 40 and 50 weeks of age. In lesions from 40-week-old mice, mRNA expression levels of several genes in the proteasome degradation pathway were higher in hCRP(+/0)Apob(100/100)Ldlr(-1-) mice than in littermate controls, as shown by global gene expression profiles. These results were confirmed by real-time PCR, which also indicated that the activities of those genes were the same at 30 and 40 weeks in hCRP(+/0)Apob(100/100)Ldlr(-1-) mice but were significantly lower at 40 weeks than at 30 weeks in controls. Our results show that hCRP is not proatherogenic but instead slows atherogenesis, possibly through proteasome-mediated protein degradation.