Brief report: accelerated atherosclerosis in low-density lipoprotein receptor-deficient mice lacking the membrane-bound complement regulator CD59.
OBJECTIVE
Whereas studies in humans and animal models have suggested a role for complement activation in atherosclerosis, there has been little analysis of the importance of complement regulators. We tested the hypothesis that the terminal pathway inhibitor CD59 plays an essential role in limiting the proinflammatory effects of complement activation.


RESULTS
CD59 gene targeted mice (CD59a(-/-)) mice were crossed with low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice. CD59-deficient Ldlr(-/-) mice had significantly more extensive en face Sudan IV staining of thoracoabdominal aorta than Ldlr(-/-) single knock-outs, both after a low-fat diet (6.51+/-0.36% versus 2.63+/-0.56%, P<0.001) or a high-fat diet (17.05+/-2.15% versus 7.69+/-1.17%, P<0.004). Accelerated lesion formation in CD59a(-/-)/Ldlr(-/-) mice on a high-fat diet was associated with increased lesional vascular smooth muscle cell (VSMC) number and fibrous cap formation.


CONCLUSIONS
Our data show that CD59 deficiency accelerates the development of lesions and increases plaque VSMC composition. Assuming that the main function of CD59 is to prevent the development of C5b-9 membrane attack complexes, our observations are consistent with the terminal complement pathway having proatherogenic potential in the Ldlr(-/-) mouse model, and highlight the importance of complement regulation.
Yun
Sheng
S
NHLI Cardiovascular Sciences, Imperial College, Hammersmith Hospital, Du Cane Road, London, UK.
Leung
Viola W Y
VW
Botto
Marina
M
Boyle
Joseph J
JJ
Haskard
Dorian O
DO
D000818:Animals; D001013:Aorta, Thoracic / Q000276:immunology / Q000378:metabolism; D050197:Atherosclerosis / Q000209:etiology / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D018957:CD59 Antigens / Q000235:genetics* / Q000378:metabolism*; D003433:Crosses, Genetic; D004041:Dietary Fats; D004195:Disease Models, Animal; D018450:Disease Progression; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000276:immunology / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D018957:CD59 Antigens; D004041:Dietary Fats; D011973:Receptors, LDL