Brief Report: Accelerated Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient Mice Lacking the Membrane-Bound Complement Regulator CD59

Abstract

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. Methods and Results-CD59 gene targeted mice (CD59a Ϫ/Ϫ ) mice were crossed with low-density lipoprotein receptordeficient (Ldlr Ϫ/Ϫ ) mice. CD59-deficient Ldlr Ϫ/Ϫ mice had significantly more extensive en face Sudan IV staining of thoracoabdominal aorta than Ldlr Ϫ/Ϫ single knock-outs, both after a low-fat diet (6.51Ϯ0.36% versus 2.63Ϯ0.56%, PϽ0.001) or a high-fat diet (17.05Ϯ2.15% versus 7.69Ϯ1.17%, PϽ0.004). Accelerated lesion formation in CD59a Ϫ/Ϫ /Ldlr Ϫ/Ϫ mice on a high-fat diet was associated with increased lesional vascular smooth muscle cell (VSMC) number and fibrous cap formation. Conclusion-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 Ϫ/Ϫ mouse model, and highlight the importance of complement regulation.

Decay-Accelerating Factor Suppresses Complement C3 Activation and Retards Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient Mice

“…As in our previous studies with C1q and CD59 deficiencies, these changes were most marked in mice fed a low-fat diet. 24,41 Taking the three studies together, the data are consistent with a homeostatic role for the classical complement pathway in the arterial wall on a low-fat diet, which is overridden by the greater inflammatory milieu caused by high fat feeding.…”

“…21,40,41 In this article, we show that DAF also plays a role in the regulation of atherosclerosis in the Ldlr Ϫ/Ϫ model. All mice in the study were female.…”

“…In general, the phenotype of daf-1 Ϫ/Ϫ Ldlr Ϫ/Ϫ mice was similar to that which we have previously reported for mice lacking CD59, apart from a greater prominence of VSMC in the aortic root lesions of high fat diet fed mice in the latter. 41 The cause for this is not clear, but could relate to the capacity of CD59 to protect VSMC from the established pro-proliferative signaling effects of C5b-9. 2,52 In this respect it is notable that VSMC showed only low level DAF expression, in contrast to a high level of CD59 expression seen previously.…”

“…En face staining of thoracoabdominal aorta and quantification of the aortic root lesion area were conducted as described. 24,41 Immunohistochemistry was performed by standard procedures on residual sections not required for analysis of lesion size, as described. 24,41 Results of immunocytochemistry are presented as a percentage area fraction of the aortic root or as the percentage of lesional cells, as analyzed by Image ProPlus software above.…”

“…The experimental groups were gradually transferred onto low-fat or high-fat diets at 10 weeks of age, as described. 41 All mice were studied at 22 weeks of age.…”