Decay‐Accelerating Factor plays a critical atheroprotective role in Low Density Lipoprotein deficient (ldlr−/−) mice

Abstract

Background: The GPI‐anchored membrane glycoprotein Decay‐Accelerating Factor (DAF, CD55) inhibits complement activation by downregulating C3 and C5 convertases. We asked whether DAF × LDLR double knock‐out (DKO) mice are protected from atherosclerosis.Methods and Results: Immunostaining showed expression of DAF by endothelial cells, macrophages and vascular smooth muscle cells in ldlr−/− but not in DKO. At 22 weeks on a chow diet, DKO mice had more en face Sudan IV staining of thoracoabdominal aorta than LDLR single knock‐outs (4.66 ± 0.63% vs 2.85 ± 0.34%, mean ± SEM, p<0.05). Accelerated lesion formation in DKO mice was also evident in aortic roots, with lesions being larger (76.16 ± 9.53 × 103 μm2 vs. 29.42 ± 3.83 × 103 μm2, mean ± SEM, p<0.0005) and more complex (vascular smooth muscle cell content 13.86 ± 5.82 % vs. 2.23 ± 1.54 %, p<0.0005). DKO mice had increased aortic root C3d staining (% lesion positive for C3d 11.5 ± 1.3% vs 3.0 ± 0.2%, p < 0.001), and higher levels of IL1β and TNFα (p<0.01 each).Conclusion: Our data indicate that DAF plays a critical role in regulating C3 activation in the arterial wall. Effective complement regulation enables the protective actions of the classical complement pathway on debris clearance to occur whilst reducing deleterious proinflammatory downstream effects of C3 activation.Funded by the British Heart Foundation