Decay-accelerating factor suppresses complement C3 activation and retards atherosclerosis in low-density lipoprotein receptor-deficient mice.
Decay-accelerating factor (DAF; CD55) is a membrane protein that regulates complement pathway activity at the level of C3. To test the hypothesis that DAF plays an essential role in limiting complement activation in the arterial wall and protecting from atherosclerosis, we crossed DAF gene targeted mice (daf-1(-/-)) with low-density lipoprotein-receptor deficient mice (Ldlr(-/-)). Daf-1(-/-)Ldlr(-/-) mice had more extensive en face Sudan IV staining of the thoracoabdominal aorta than Ldlr(-/-) mice, both following a 12-week period of low-fat diet or a high-fat diet. Aortic root lesions in daf-1(-/-)Ldlr(-/-) mice on a low-fat diet showed increased size and complexity. DAF deficiency increased deposition of C3d and C5b-9, indicating the importance of DAF for downstream complement regulation in the arterial wall. The acceleration of lesion development in the absence of DAF provides confirmation of the proinflammatory and proatherosclerotic potential of complement activation in the Ldlr(-/-) mouse model. Because upstream complement activation is potentially protective, this study underlines the importance of DAF in shielding the arterial wall from the atherogenic effects of complement.
Leung
Viola W Y
VW
Vascular Science Section, Imperial College, National Heart and Lung Institute, the Division of Investigative Sciences, Imperial College London, Hammersmith Hospital, London W12 0NN, United Kingdom.
Yun
Sheng
S
Botto
Marina
M
Mason
Justin C
JC
Malik
Talat H
TH
Song
Wenchao
W
Paixao-Cavalcante
Danielle
D
Pickering
Matthew C
MC
Boyle
Joseph J
JJ
Haskard
Dorian O
DO
D000199:Actins / Q000378:metabolism; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001012:Aorta, Abdominal / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D001013:Aorta, Thoracic / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D050197:Atherosclerosis / Q000097:blood / Q000276:immunology* / Q000517:prevention & control*; D001835:Body Weight / Q000187:drug effects; D018958:CD55 Antigens / Q000378:metabolism*; D003167:Complement Activation / Q000187:drug effects / Q000276:immunology*; D003176:Complement C3 / Q000276:immunology*; D015933:Complement C3d / Q000276:immunology; D015938:Complement Membrane Attack Complex / Q000276:immunology; D008055:Lipids / Q000097:blood; D051379:Mice; D018613:Microscopy, Confocal; D011973:Receptors, LDL / Q000172:deficiency* / Q000378:metabolism; D015203:Reproducibility of Results
D000199:Actins; D000906:Antibodies; D018958:CD55 Antigens; D003176:Complement C3; D015938:Complement Membrane Attack Complex; D008055:Lipids; D011973:Receptors, LDL; D015933:Complement C3d