The Alternative Pathway Is Critical for Pathogenic Complement Activation in Endotoxin- and Diet-Induced Atherosclerosis in Low-Density Lipoprotein Receptor–Deficient Mice

Background— The early components of the classical and lectin complement pathways have been shown to protect low-density lipoprotein receptor–deficient mice (Ldlr −/− ) from early atherogenesis. However, the role of the alternative pathway remained unknown, and that was investigated in this study.Methods and Results— Mice lacking factor B (Bf −/− ), the initiator of the alternative pathway, were crossed withLdlr −/− mice and studied under different proatherogenic conditions. There was no statistically significant difference in lipid profiles or atherosclerotic lesion development betweenBf −/− /Ldlr −/− andLdlr −/− mice fed a low-fat diet. However, in these groups, administration of bacterial lipopolysaccharide led to a significant increase in atherosclerosis only inLdlr −/− and not inBf −/− /Ldlr −/− mice, indicating that the alternative pathway is necessary for endotoxin-mediated atherogenesis.Bf −/− /Ldlr −/− mice also had significantly decreased cross-sectional aortic root lesion fraction area and reduced lesion complexity compared withLdlr −/− animals after a 12-week period of high-fat diet, although this was also accompanied by reduced levels of serum cholesterol. Under both experimental conditions, the atherosclerotic changes in theBf −/− /Ldlr −/− mice were accompanied by a marked reduction in complement activation in the circulation and in atherosclerotic plaques, with no statistically significant differences in immunoglobulin G deposition or in the serum antibody response to oxidized low-density lipoprotein.Conclusions— These data demonstrate that amplification of complement activation by the alternative pathway in response to lipopolysaccharide or high-fat diet plays a proatherogenic role.