Journal
MOLECULAR IMMUNOLOGY
Volume 46, Issue 8-9, Pages 1702-1709Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.molimm.2009.02.009
Keywords
Complement; CD59; DAF; ApoE; Atherosclerosis
Categories
Funding
- National Institutes of Health [AI-49344, AI-44970, AI-62388]
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Although the complement system has been implicated in atherosclerosis, the influence of membrane-bound complement regulators in this process has not been well understood. We studied the role of two membrane complement regulators, decay-accelerating factor (DAF) and CD59, in a murine model of atherosclerosis. DAF(-/-) and CD59(-/-) mice were crossed with apolipoprotein E (ApoE)-deficient mice to generate DAF(-/-)ApoE(-/-) and CD59(-/-)ApoE(-/-) mice. Mice were fed a high fat diet (HFD) for 8 or 16 weeks. En face analysis showed that CD59 deficiency led to more extensive lesions in female ApoE(-/-) mice both at 8 weeks (2.07 +/- 0.27% vs.1.34 +/- 0.21%, P = 0.06) and 16 weeks (17.13 +/- 1.14% vs. 9.72 +/- 1.14%, P<0.001). Similarly, lesions measured by aortic root sectioning were larger in female CD59-/-ApoE-/- mice than in controls at 8 weeks of HFD feeding (20.74 +/- 1.33% vs. 13.12 +/- 1.46%, P<0.005). On the other hand, DAF deficiency did not significantly influence atherosclerosis in ApoE(-/-) mice. Immunohistochemistry revealed more abundant membrane attack complex (MAC) deposition and more collagen staining in the aortic roots of CD59(-/-)ApoE(-/-) mice. Unexpectedly, total plasma cholesterol levels in female CD59(-/-)ApoE(-/-) mice were found to be elevated compared with CD59(-/-)ApoE(-/-) mice. We conclude that CD59 but not DAF offered protection in atherosclerosis in the context of ApoE deficiency. The protective role of CD59 was gender-biased and most likely involved prevention of MAC-mediated vascular injury, with possible contribution from an undefined effect on plasma cholesterol homeostasis. (C) 2009 Elsevier Ltd. All rights reserved.
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