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.
An
Guipeng
G
Institute for Translational Medicine and Therapeutics and Department of Pharmacology, University of Pennsylvania School of Medicine, Room 1254 BRBII/III, 421 Curie Blvd, Philadelphia, PA 19104, USA.
Miwa
Takashi
T
Song
Wen-Liang
WL
Lawson
John A
JA
Rader
Daniel J
DJ
Zhang
Yun
Y
Song
Wen-Chao
WC
D000818:Animals; D001011:Aorta / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics*; D050197:Atherosclerosis / Q000097:blood / Q000235:genetics* / Q000473:pathology; D018958:CD55 Antigens / Q000235:genetics* / Q000502:physiology; D018957:CD59 Antigens / Q000235:genetics* / Q000502:physiology; D002784:Cholesterol / Q000097:blood; D018450:Disease Progression; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012727:Sex Characteristics; D013997:Time Factors
D001057:Apolipoproteins E; D018958:CD55 Antigens; D018957:CD59 Antigens; D002784:Cholesterol