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.


RESULTS
Mice lacking factor B (Bf(-/-)), the initiator of the alternative pathway, were crossed with Ldlr(-/-) mice and studied under different proatherogenic conditions. There was no statistically significant difference in lipid profiles or atherosclerotic lesion development between Bf(-/-)/Ldlr(-/-) and Ldlr(-/-) mice fed a low-fat diet. However, in these groups, administration of bacterial lipopolysaccharide led to a significant increase in atherosclerosis only in Ldlr(-/-) and not in Bf(-/-)/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 with Ldlr(-/-) 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 the Bf(-/-)/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.
Malik
Talat H
TH
Rheumatology Section, Division of Immunology and Inflammation, Department of Medicine, Imperial College, London, UK.
Cortini
Andrea
A
Carassiti
Daniele
D
Boyle
Joseph J
JJ
Haskard
Dorian O
DO
Botto
Marina
M
D000818:Animals; D000906:Antibodies / Q000097:blood; D050197:Atherosclerosis / Q000097:blood / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology*; D003167:Complement Activation / Q000235:genetics / Q000502:physiology; D003176:Complement C3 / Q000378:metabolism; D015926:Complement C3a / Q000378:metabolism; D011415:Complement Factor B / Q000172:deficiency; D003170:Complement Pathway, Alternative / Q000276:immunology* / Q000502:physiology; D003165:Complement System Proteins / Q000378:metabolism; D004036:Diet, Atherogenic; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D007249:Inflammation / Q000276:immunology / Q000503:physiopathology; D008070:Lipopolysaccharides / Q000633:toxicity; D008077:Lipoproteins, LDL / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000172:deficiency*
D000906:Antibodies; D003176:Complement C3; D007074:Immunoglobulin G; D008070:Lipopolysaccharides; D008077:Lipoproteins, LDL; D011973:Receptors, LDL; C099252:oxidized low density lipoprotein; D015926:Complement C3a; D003165:Complement System Proteins; D011415:Complement Factor B