Shagdarsuren Erdenechimeg, Bidzhekov Kiril, Djalali-Talab Yassin, Liehn Elisa A, Hristov Mihail, Matthijsen Robert A, Buurman Wim A, Zernecke Alma, Weber Christian
Institute of Molecular Cardiovascular Research, University Hospital, RWTH Aachen University, Aachen, Germany.
Circulation. 2008 Jan 1;117(1):70-8. doi: 10.1161/CIRCULATIONAHA.107.715649. Epub 2007 Dec 10.
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).
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 i.v.) 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.
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.
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作用尚未得到研究。在此，我们使用C1酯酶抑制剂（C1抑制剂）研究了补体级联反应在载脂蛋白E缺陷小鼠新内膜形成中的作用。
给喂食致动脉粥样硬化饮食的载脂蛋白E缺陷小鼠进行颈动脉钢丝诱导的内皮剥脱术，并在围手术期及随后每2天用C1抑制剂（贝林妥欧；15国际单位静脉注射）或赋形剂进行治疗。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。在接受C1抑制剂治疗的小鼠中观察到血清甘油三酯水平显著降低，而胆固醇水平无差异。3周后，与对照组相比，接受C1抑制剂治疗的小鼠新内膜面积显著减小，而中膜面积未改变。这与新内膜和中膜巨噬细胞及CD3 + T细胞含量的显著降低有关。通过逆转录聚合酶链反应评估，损伤后10天，接受C1抑制剂治疗的小鼠斑块中C3 mRNA表达显著降低。ELISA结果表明，C1抑制剂显著下调了损伤后血清C3水平的峰值。免疫组织化学显示C3和C3c表达强烈，它们与斑块巨噬细胞共定位，且在接受C1抑制剂治疗的小鼠中减少。C1抑制剂在体外流动条件下损害单核细胞在活化内皮和血小板上的黏附，并在体内损伤后1天损害白细胞向颈动脉的募集。
C1抑制剂可限制新内膜斑块形成和炎症。这可能涉及补体激活的阻断、白细胞募集的抑制以及甘油三酯水平的降低，从而为治疗动脉疾病提供了一种多模式方法。
