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Circulation. 2010 Nov 9;122(19):1948-56. doi: 10.1161/CIRCULATIONAHA.110.981365. Epub 2010 Oct 25.

The alternative pathway is critical for pathogenic complement activation in endotoxin- and diet-induced atherosclerosis in low-density lipoprotein receptor-deficient mice.

Author information

1
Rheumatology Section, Division of Immunology and Inflammation, Department of Medicine, Imperial College, London, UK.

Erratum in

  • Circulation. 2011 Dec 6;124(23):e781.

Abstract

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 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.

PMID:
20974996
PMCID:
PMC2978131
DOI:
10.1161/CIRCULATIONAHA.110.981365
[Indexed for MEDLINE]
Free PMC Article

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