C1-esterase inhibitor protects against neointima formation after arterial injury in atherosclerosis-prone mice
C1-esterase inhibitor protects against neointima formation after arterial injury in atherosclerosis-prone mice
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DOI：
10.1161/circulationaha.107.715649
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发表时间：
2008-01-01
期刊：
影响因子：
37.8
通讯作者：
Weber, Christian
中科院分区：
文献类型：
--
作者：
Shagdarsuren, Erdenechimeg;Bidzhekov, Kiril;Weber, Christian
背景--尽管补体系统的激活与人类动脉粥样硬化的进展有关，但其在损伤后动脉重塑过程中的功能尚未得到研究。在这里，我们研究了补体级联反应的贡献载脂蛋白E-缺乏小鼠使用C1-酯酶抑制剂（C1-inhibitor）. Methods和Results-Apoprotein E-缺乏小鼠喂养动脉粥样硬化饮食进行线诱导的颈动脉内皮剥脱和治疗C1-抑制剂（Berinert; 15 IU IV）或车辆围手术期和随后每2天。通过测量血浆C1抑制剂活性证实了C1抑制剂治疗的有效性。在C1-胆固醇处理的小鼠中观察到血清甘油三酯水平显著降低，而胆固醇水平没有差异。3周后，与对照组相比，C1-受体处理的小鼠的新生内膜面积显著减少，而中膜面积没有改变。这与新生内膜和中膜巨噬细胞和CD3 + T细胞含量显著降低相关。C3 mRNA的表达显着减少斑块的C1-受体处理的小鼠损伤后10天，通过逆转录聚合酶链反应评估。损伤后血清C3水平的峰值明显下调C1-抑制剂，如ELISA证明。免疫组织化学显示C3和C3c的强表达，其共定位于斑块巨噬细胞，并且在C1-受体处理的小鼠中减少。C1-抑制剂受损的单核细胞逮捕激活的内皮细胞和血小板在体外流动条件下和白细胞招聘到颈动脉1天后injured.Conclusions-C1-抑制剂限制新生内膜斑块的形成和炎症。这可能涉及阻断补体激活、抑制白细胞募集和降低甘油三酯水平，从而提供治疗动脉疾病的多模式方法。
Background-Although activation of the complement system has been implicated in the progression of human atherosclerosis, its function during arterial remodeling after injury has not been investigated. Here, we examined the contribution of the complement cascade to neointima formation in apolipoprotein E-deficient mice using a C1-esterase inhibitor (C1-inhibitor).Methods and Results-Apolipoprotein E-deficient mice fed an atherogenic diet were subjected to wire-induced endothelial denudation of the carotid artery and treated with C1-inhibitor (Berinert; 15 IU IV) or vehicle perioperatively and subsequently every 2 days. The effectiveness of C1-inhibitor treatment was confirmed by measurement of plasma C1-inhibitor activity. A significant reduction in serum triglyceride levels was observed in C1-inhibitor-treated mice, whereas cholesterol levels did not differ. After 3 weeks, neointimal area was significantly reduced in C1-inhibitor-treated mice versus controls, whereas medial area was unaltered. This was associated with a significant decrease in neointimal and medial macrophage and CD3+ T-cell content. Expression of C3 mRNA was significantly reduced in plaques of C1-inhibitor-treated mice 10 days after injury, as assessed by reverse-transcription polymerase chain reaction. The peak in serum C3 levels after injury was markedly downregulated by C1-inhibitor, as evidenced by ELISA. Immunohistochemistry revealed strong expression of C3 and C3c, which colocalized to plaque macrophages and was reduced in C1-inhibitor-treated mice. C1-inhibitor impaired monocyte arrest on activated endothelium and platelets under flow conditions in vitro and leukocyte recruitment to carotid arteries 1 day after injury in vivo.Conclusions-C1-inhibitor limits neointimal plaque formation and inflammation. This may involve blockade of complement activation, inhibition of leukocyte recruitment, and reduced triglyceride levels, thus providing a multimodal approach to treat arterial disease.