Accelerated Atherosclerosis in Low Density Lipoprotein Receptor Deficient Mice Lacking the Membrane Complement Regulator CD59

Abstract

Background: CD59 is a membrane glycoprotein that inhibits terminal complement pathway C5b‐9 assembly. Here, we tested the hypothesis that CD59 limits the proinflammatory effects of complement activation in atherosclerosis.Methods and Results: CD59 gene targeted mice (CD59a−/−) mice were crossed with Ldlr−/− mice to give double knock‐outs (DKO), and studied aged 22 weeks. Immunocytochemical staining showed CD59 on endothelial cells, vascular smooth muscle cells (VSMC) and macrophages in Ldlr−/− mice, with absent staining in DKO. DKO had more extensive en face Sudan IV staining of thoraco‐abdominal aorta than Ldlr−/− single knock‐outs, both following a normal chow (6.51 + 0.36% vs 2.63 + 0.56%, p<0.0001) or a high fat diet (17.05 + 2.15% vs 7.69 + 1.17%, p<0.02). Accelerated lesion formation in DKO mice was associated with significantly increased complexity of lesions in the aortic root, as assessed by increased VSMC number and fibrous caps development. The acceleration of atherosclerosis in DKO mice was associated with significantly greater deposition of C5b‐9, both following a chow or a high fat diet.Conclusion: The acceleration of lesion formation in the absence of CD59 provides definitive evidence for complement activation in the Ldlr−/− mouse model and underlines the importance of CD59 in protection from the proatherogenic effects of the terminal complement pathway.Funded by the British Heart Foundation