The alternative pathway is critical for pathogenic complement activation in endotoxin- and diet-induced atherosclerosis in low-density lipoprotein receptor-deficient mice.
The alternative pathway is critical for pathogenic complement activation in endotoxin- and diet-induced atherosclerosis in low-density lipoprotein receptor-deficient mice.
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DOI：
10.1161/circulationaha.110.981365
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发表时间：
2010-11-09
期刊：
影响因子：
37.8
通讯作者：
Botto M
中科院分区：
文献类型：
--
作者：
Malik TH;Cortini A;Carassiti D;Boyle JJ;Haskard DO;Botto M
经典补体途径和凝集素补体途径的早期成分已被证明可以保护低密度脂蛋白受体缺陷小鼠（Ldlr−/−）免受早期动脉粥样硬化的影响。然而，旁路途径的作用仍然未知，本研究对其进行了研究。缺乏因子B（Bf-/-）的小鼠，旁路途径的启动者，与Ldlr-/-小鼠杂交，并在不同的促动脉粥样硬化条件下进行研究。在低脂饮食喂养的Bf−/−、Ldlr−/−和Ldlr−/−小鼠之间，血脂谱或动脉粥样硬化病变发展没有统计学显著差异。然而，在这些组中，细菌脂多糖（LPS）的施用仅导致Ldlr−/−小鼠的动脉粥样硬化显著增加，而在Bf−/−.Ldlr−/−小鼠中没有，表明替代途径是内毒素介导的动脉粥样硬化形成所必需的。与Ldlr −/−动物相比，Bf−/−.Ldlr −/−小鼠在12周的高脂饮食后也显著降低了横截面主动脉根病变分数面积和病变复杂性，尽管这也伴随着血清胆固醇水平的降低。在这两种实验条件下，Bf−/−.Ldlr−/−小鼠的动脉粥样硬化变化伴随着循环和动脉粥样硬化斑块中补体激活的显著减少，IgG沉积或对氧化LDL的血清抗体反应没有统计学显著差异。这些数据表明，通过旁路途径对LPS或高脂饮食应答的补体激活的放大起促动脉粥样硬化作用。
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. Mice lacking factor B (Bf−/−), the initiator of the alternative pathway, were crossed with Ldlr−/− mice and studied under different pro-atherogenic 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 (LPS) 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 to 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 statistical significant differences in IgG deposition or in the serum antibody response to oxidised LDL. These data demonstrate that amplification of complement activation by the alternative pathway in response to LPS or high fat diet plays a pro-atherogenic role.