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Atherosclerosis. 2014 May;234(1):237-43. doi: 10.1016/j.atherosclerosis.2014.03.004. Epub 2014 Mar 15.

Targeted mouse complement inhibitor CR2-Crry protects against the development of atherosclerosis in mice.

Author information

1
Department of Immunology, Shandong University School of Medicine, #44 Wenhua Xi Road, Jinan, Shandong 250012, PR China; Department of Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA; Department of Neuroscience, Temple University School of Medicine, Philadelphia, PA 19140, USA.
2
Department of Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA; Department of Hematology, Shanghai Jiao Tong University Affiliated First People's Hospital, Shanghai 200080, PR China.
3
Department of Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA.
4
Department of Hematology, Shanghai Jiao Tong University Affiliated First People's Hospital, Shanghai 200080, PR China.
5
Department of Immunology, Shandong University School of Medicine, #44 Wenhua Xi Road, Jinan, Shandong 250012, PR China.
6
Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA; Ralph A. Johnson Veterans Affairs Medical Center, Charleston, SC 29401, USA. Electronic address: tomlinss@musc.edu.
7
Department of Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA; Department of Neuroscience, Temple University School of Medicine, Philadelphia, PA 19140, USA. Electronic address: xuebin.qin@temple.edu.

Abstract

OBJECTIVE:

Atherosclerosis is a chronic inflammatory and immune vascular disease, and clinical and experimental evidence has indicated an important role of complement activation products, including the terminal membrane attack complex (MAC), in atherogenesis. Here, we investigated whether complement inhibition represents a potential therapeutic strategy to treat/prevent atherogenesis using CR2-Crry, a recently described complement inhibitor that specifically targets to sites of C3 activation.

METHODS AND RESULTS:

Previous studies demonstrated that loss of CD59 (a membrane inhibitor of MAC formation) accelerated atherogenesis in Apoe deficient (Apoe(-/-)) mice. Here, both CD59 sufficient and CD59 deficient mice in an Apoe deficient background (namely, mCd59 ab(+/+)/Apoe(-/-) and mCd59 ab(-/-)/Apoe(-/-)) were treated with CR2-Crry for 4 and 2 months respectively, while maintained on a high fat diet. Compared to control treatment, CR2-Crry treatment resulted in significantly fewer atherosclerotic lesions in the aorta and aortic root, and inhibited the accelerated atherogenesis seen in mCd59 ab(+/+)/Apoe(-/-) and mCd59 ab(-/-)/Apoe(-/-) mice. CR2-Crry treatment also resulted in significantly reduced C3 and MAC deposition in the vasculature of both mice, as well as a significant reduction in the number of infiltrating macrophages and T cells.

CONCLUSION:

The data demonstrate the therapeutic potential of targeted complement inhibition.

KEYWORDS:

Atherosclerosis; CD59 and therapeutics; Complement; Complement regulation; Crry

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