Reversal of hyperlipidemia with a genetic switch favorably affects the content and inflammatory state of macrophages in atherosclerotic plaques.
Reversal of hyperlipidemia with a genetic switch favorably affects the content and inflammatory state of macrophages in atherosclerotic plaques.
复制标题
具有遗传转换的高脂血症的逆转会影响动脉粥样硬化斑块中巨噬细胞的含量和炎症状态。
DOI：
10.1161/circulationaha.110.984146
复制
发表时间：
2011-03-08
期刊：
影响因子：
37.8
通讯作者：
Fisher EA
中科院分区：
文献类型：
--
作者：
Feig JE;Parathath S;Rong JX;Mick SL;Vengrenyuk Y;Grauer L;Young SG;Fisher EA
我们以前的研究表明，当高脂血症通过灭活微粒体甘油三酯转移蛋白基因而正常化时，逆转小鼠(Ldlr−/−Apob100/100Mttpfl/flMx1Cre+/+)的动脉粥样硬化进程被阻止。在这里，我们测试了如果在晚期斑块形成后降低血脂水平，动脉粥样硬化是否会消退。给Reversa小鼠喂食致动脉粥样硬化饲料16周。然后，降低了血脂水平。在2周内，这种减少导致动脉粥样硬化斑块中单核细胞衍生(CD68+)细胞减少，并与这些细胞从斑块中迁出有关。此外，随着血脂水平的下降，斑块中脂质含量降低，斑块CD68+细胞中炎性基因表达减少，抗炎M2巨噬细胞标志物基因表达增加。斑块组成比斑块大小受到的影响更大，脂质和CD68+细胞含量的下降被较高的胶原含量所平衡。当降脂与吡格列酮联合应用模拟临床侵袭性血脂管理和γ激动剂治疗时，斑块CD6 8+细胞的去化率未受影响，但其抗炎巨噬细胞标志物的表达进一步增加。逆转小鼠模型是一种新的动脉粥样硬化消退模型。降脂后，斑块成分的有利变化与大小的变化无关。此外，斑块CD68+细胞炎症减轻，用吡格列酮治疗后这种效果增强。
We previously showed that the progression of atherosclerosis in the Reversa mouse (Ldlr−/−Apob100/100Mttpfl/flMx1Cre+/+) was arrested when the hyperlipidemia was normalized by inactivating the gene for microsomal triglyceride transfer protein. Here we tested whether atherosclerosis would regress if the lipid levels were reduced after advanced plaques formed. Reversa mice were fed an atherogenic diet for 16 weeks. Plasma lipid levels were then reduced. Within 2 weeks, this reduction led to decreased monocyte-derived (CD68+) cells in atherosclerotic plaques and was associated with emigration of these cells out of plaques. Also, the fall in lipid levels was accompanied by lower plaque lipid content and by reduced expression in plaque CD68+ cells of inflammatory genes and higher expression of genes for markers of anti-inflammatory M2 macrophages. Plaque composition was affected more than plaque size, with the decreased content of lipid and CD68+ cells balanced by a higher content of collagen. When a reduced lipid levels was combined with the administration of pioglitazone to simulate the clinical aggressive lipid management and PPARγ agonist treatment, the rate of depletion of plaque CD68+ cells was unaffected, but there was a further increase in their expression of anti-inflammatory macrophage markers. The Reversa mouse model is a new model of atherosclerosis regression. After lipid lowering favorable changes in plaque composition were independent of changes in size. In addition, plaque CD68+ cells became less inflammatory, an effect enhanced by treatment with pioglitazone.