Complement C1q reduces early atherosclerosis in low-density lipoprotein receptor-deficient mice
Complement C1q reduces early atherosclerosis in low-density lipoprotein receptor-deficient mice
复制标题
DOI：
10.2353/ajpath.2007.060406
复制
发表时间：
2007-01-01
影响因子：
6
通讯作者：
Haskard, Dorian O.
中科院分区：
文献类型：
--
作者：
Bhatia, Vinay K.;Yun, Sheng;Haskard, Dorian O.
我们通过将C1 q缺陷小鼠（C1 qa（-/-））与低密度脂蛋白受体敲除小鼠（Ldlr（-/-））杂交，探索经典补体途径在动脉粥样硬化形成中的作用。给小鼠喂食正常啮齿动物饮食直到22周龄。C1 qa（-/-）/Ldlr（-/-）小鼠的主动脉根部病变是Ldlr（-/-）小鼠的3倍（3.72 +/- 1.0%主动脉根部对1.1 +/- 0.4%;平均值+/- SEM，P < 0.001）。此外，C1 qa（-/-）/ Ldlr（-/-）病变的细胞组成更复杂，血管平滑肌细胞增加。C1 qa（-/-）/Ldlr（-/-）小鼠的主动脉根部病变尺寸更大，尽管每病变单位面积的C5 b-9沉积显著减少，表明近端通路活性至关重要。在C1 qa（-/-）/Ldlr（-/-）小鼠中，通过裂解的caspase-3染色、末端脱氧核苷酸转移酶dUTP缺口末端标记试验和电子显微镜可容易地检测到凋亡细胞，而在Ldlr（-/-）小鼠中未检测到凋亡细胞。这是第一次直接证明经典补体途径在动脉粥样硬化形成中的作用。C1 qa（-/-）/Ldlr（-/-）小鼠中较大的病变大小与C1 q在处理垂死细胞中的新兴稳态作用一致。这项研究表明，有效的凋亡细胞去除的重要性，包含在动脉粥样硬化的早期病变的大小和复杂性。
We explored the role of the classic complement pathway in atherogenesis by intercrossing C1q-deficient mice (C1qa(-/-)) with low-density lipoprotein receptor knockout mice (Ldlr(-/-)). Mice were fed a normal rodent diet until 22 weeks of age. Aortic root lesions were threefold larger in C1qa(-/-)/Ldlr(-/-) mice compared with Ldlr(-/-) mice (3.72 +/- 1.0% aortic root versus 1.1 +/- 0.4%; mean +/- SEM, P < 0.001). Furthermore, the cellular composition of lesions in C1qa(-/-)/ Ldlr(-/-) was more complex, with an increase in vascular smooth muscle cells. The greater aortic root lesion size in C1qa(-/-)/Ldlr(-/-) mice occurred despite a significant reduction in C5b-9 deposition per lesion unit area, suggesting the critical importance of proximal pathway activity. Apoptotic cells were readily detectable by cleaved caspase-3 staining, terminal deoxynucleotidyl transferase dUTP nick-end labeling assay, and electron microscopy in C1qa(-/-)/Ldlr(-/-), whereas apoptotic cells were not detected in Ldlr(-/-) mice. This is the first direct demonstration of a role for the classic complement pathway in atherogenesis. The greater lesion size in C1qa(-/-) /Ldlr(-/-) mice is consistent with the emerging homeostatic role for C1q in the disposal of dying cells. This study suggests the importance of effective apoptotic cell removal for containing the size and complexity of early lesions in atherosclerosis.