D-4F decreases brain arteriole inflammation and improves cognitive performance in LDL receptor-null mice on a Western diet
D-4F decreases brain arteriole inflammation and improves cognitive performance in LDL receptor-null mice on a Western diet
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DOI：
10.1194/jlr.m600214-jlr200
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发表时间：
2006-10-01
影响因子：
6.5
通讯作者：
Fogelman, Alan M.
中科院分区：
文献类型：
--
作者：
Buga, Georgette M.;Frank, Joy S.;Fogelman, Alan M.
接受西式饮食（WD）的低密度脂蛋白受体缺失小鼠出现大动脉炎症和小动脉内皮功能障碍，而载脂蛋白A-I模拟物D-4F可以改善这些情况。高脂血症在引起非常小的血管（如脑小动脉）炎症中的作用以前尚未研究过。WD引起脑内微动脉和相关巨噬细胞（小胶质细胞）百分比的显著增加（P < 0.01），口服D-4F可降低微动脉和相关巨噬细胞（小胶质细胞）的百分比，但乱序D-4F不能降低微动脉和相关巨噬细胞（小胶质细胞）的百分比（P < 0.01）。D-4F（而不是ScD-4F）降低与CCL 3/巨噬细胞炎性蛋白-1 α（P < 0.01）和CCL 2/单核细胞趋化蛋白-1（P < 0.001）相关的脑小动脉的百分比。A WD使脑小动脉壁厚度和平滑肌α-actin增加（P < 0.001），D-4F使其减少，而ScD-4F则无此作用（P> 0.0001）。D-4F治疗组的血脂水平、血压或小动脉管腔直径无差异。在T-迷宫连续交替任务和Morris水迷宫中的认知能力被WD损害，而D-4F显著改善，但ScD-4F没有改善（P < 0.05）。我们的结论是，WD诱导脑小动脉炎症和认知障碍，改善口服D-4F不改变血脂，血压，或小动脉管腔大小。
LDL receptor-null mice on a Western diet (WD) have inflammation in large arteries and endothelial dysfunction in small arteries, which are improved with the apolipoprotein A-I mimetic D-4F. The role of hyperlipidemia in causing inflammation of very small vessels such as brain arterioles has not previously been studied. A WD caused a marked increase in the percent of brain arterioles with associated macrophages (microglia) (P < 0.01), which was reduced by oral D-4F but not by scrambled D-4F (ScD-4F; P < 0.01). D-4F (but not ScD-4F) reduced the percent of brain arterioles associated with CCL3/macrophage inflammatory protein-1 alpha (P < 0.01) and CCL2/monocyte chemoattractant protein-1 (P < 0.001). A WD increased (P < 0.001) brain arteriole wall thickness and smooth muscle a-actin, which was reduced by D-4F but not by ScD-4F (P < 0.0001). There was no difference in plasma lipid levels, blood pressure, or arteriole lumen diameter with D-4F treatment. Cognitive performance in the T-maze continuous alternation task and in the Morris Water Maze was impaired by a WD and was significantly improved with D-4F but not ScD-4F (P < 0.05). We conclude that a WD induces brain arteriole inflammation and cognitive impairment that is ameliorated by oral D-4F without altering plasma lipids, blood pressure, or arteriole lumen size.