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(Circulation. 2008;117:70-78.)
© 2008 American Heart Association, Inc.

Molecular Cardiology

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

Erdenechimeg Shagdarsuren, MD; Kiril Bidzhekov, PhD; Yassin Djalali-Talab, BSc; Elisa A. Liehn, MD; Mihail Hristov, MD; Robert A. Matthijsen, MD; Wim A. Buurman, PhD; Alma Zernecke, MD^*; Christian Weber, MD^*

From the Institute of Molecular Cardiovascular Research, University Hospital, RWTH Aachen University (E.S., K.B., Y.D.T., E.A.L., M.H., A.Z., C.W.), Aachen, Germany, and Department of General Surgery, Maastricht University (R.A.M., W.A.B.), Maastricht, the Netherlands.

Correspondence to Christian Weber, MD, Institut für Kardiovaskuläre Molekularbiologie, Universitätsklinikum der RWTH Aachen, Pauwelsstraße 30, 52074 Aachen, Germany. E-mail cweber{at}ukaachen.de

Received May 17, 2007; accepted October 5, 2007.

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.

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