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FC4 The alternative pathway is critical for pathogenic complement activation in diet -induced and endotoxin-induced atherosclerosis in low-density lipoprotein receptor-deficient mice
  1. T H Malik1,
  2. A Cortini1,
  3. D Carassiti1,
  4. V W Y Leung2,
  5. M J Lewis1,
  6. D O Haskard2,
  7. M Botto1
  1. 1Rheumatology Section, Imperial College, London, UK
  2. 2BHF Cardiovascular Medicine Unit, Imperial College, London, UK

Abstract

Our previous studies have shown that the early components of the classical complement pathway protect low-density lipoprotein receptor deficient mice (Ldlr−/−) from atherogenesis when fed a low-fat diet. However, the role of the alternative pathway remains unknown. To investigate this, we crossed mice lacking the alternative pathway activator Factor B (Bf−/−) with Ldlr−/− mice. Lipid profiles after 12 weeks on a high-fat diet showed significantly reduced levels of total cholesterol (25.2%±0.9 mmol/l, n=14, vs 40.5%±1.8 mmol/l, n=17, p<0.0001) and lipoproteins (∼1.5-fold lower VLDL and LDL) in the Bf−/−.Ldlr−/− mice compared with the Ldlr−/− animals. Consistent with this, high-fat fed Bf−/−.Ldlr−/− mice had decreased cross-sectional aortic root lesion fraction area (median 12.2%, IQR 8.92% to 15.82% vs 16.3%, 14.76% to 19.74%, p=0.0016) and reduced lesion complexity. These changes were associated with reduced complement activation in the circulation and in atherosclerotic plaques. There was no difference in lipid profiles between Bf−/−.Ldlr−/− and Ldlr−/− mice fed a low-fat diet, but in these groups administration of lipopolysaccharide (LPS) led to significant increase in atherosclerosis only in Ldlr−/− and not in Bf−/−.Ldlr−/− (aortic root lesion fraction: Bf−/−.Ldlr−/−: 7.85%, range 4.93 to 15.24%, n=9; Ldlr−/−: 22.53%, range 17.36 to 25.25%, n=10, p=0.0009), indicating that the alternative pathway also has a key role in endotoxin-mediated exacerbation of disease. These data indicate that amplification of complement activation by the alternative pathway in response to diet or infection may convert the complement system from a protective to a more atherogenic role.

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