CD59 but not DAF deficiency accelerates atherosclerosis in female ApoE knockout mice

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.