C1-Esterase Inhibitor Protects Against Neointima Formation After Arterial Injury in Atherosclerosis-Prone Mice

Abstract

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 ϩ 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. (Circulation. 2008;117:70-78.)Key Words: atherosclerosis Ⅲ inflammation Ⅲ cell adhesion molecules Ⅲ complement A therosclerosis is an inflammatory disease that is strongly affected by the action of monocytes/macrophages and T cells. 1 Emerging evidence further suggests that the complement system plays a role in atherosclerosis, although its exact functions and mechanisms of action remain unclear. 2,3 In atherosclerotic plaques, activation of the classic complement pathway has been observed. In addition, mRNA of complement components, including C3 activation products and membrane attack complex, are also detectable in diseased arteries. Membrane attack complex depositions colocalize with lipoproteins, which are known to be potent activators of the complement system in the aortic intima in rabbits at early stages of atherogenesis and in human atherosclerotic lesions, 4 and they correlate with the severity of arterial damage. 5,6 Clinical Perspective p 78However, complement regulatory proteins have not been found to be upregulated in human plaque tissue. 7 ...

Macrophage-Specific Expression of Mannose-Binding Lectin Controls Atherosclerosis in Low-Density Lipoprotein Receptor–Deficient Mice

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Decay-Accelerating Factor Suppresses Complement C3 Activation and Retards Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient Mice

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Enhanced External Counterpulsation Attenuates Atherosclerosis Progression Through Modulation of Proinflammatory Signal Pathway

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