HDL promotes rapid atherosclerosis regression in mice and alters inflammatory properties of plaque monocyte-derived cells
HDL promotes rapid atherosclerosis regression in mice and alters inflammatory properties of plaque monocyte-derived cells
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DOI：
10.1073/pnas.1016086108
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发表时间：
2011-04-26
影响因子：
11.1
通讯作者：
Fisher, Edward A.
中科院分区：
文献类型：
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作者：
Feig, Jonathan E.;Rong, James X.;Fisher, Edward A.
高密度脂蛋白胆固醇（HDL-C）血浆水平与心血管疾病风险呈负相关。先前的研究表明，在动物和人类中，HDL促进动脉粥样硬化的消退。我们假设这与促进单核细胞衍生细胞（CD 68（+），主要是巨噬细胞和巨噬细胞泡沫细胞）从斑块中丢失的能力有关。为了验证这一假设，我们使用了一个已建立的动脉粥样硬化消退模型，其中载脂蛋白E缺乏的带斑块主动脉弓（apoE（-/-））小鼠（低HDL-C，高非HDL-C）移植到具有不同HDL-C和非HDL-C水平的受体小鼠中：C57 BL 6小鼠（正常HDL-C，低非HDL-C）、apoAI（-/-）小鼠（低HDL-C，低非HDL-C）或人apoAI转基因apoE（-/-）小鼠（hAI/apoE（-/-）;正常HDL-C，高非HDL-C）。值得注意的是，尽管hAI/apoE（-/-）受体中非HDL-C持续升高，但移植后1周斑块CD 68（+）细胞含量下降> 50%，而apoAI（-/-）受体小鼠尽管有低脂血症，但变化很小。HDL-C正常化后斑块CD 68（+）细胞含量的降低与其迁移和诱导其趋化因子受体CCR 7有关。此外，在从斑块中激光捕获的CD 68（+）细胞中，HDL-C的正常化导致炎症因子表达减少和M2（组织修复）巨噬细胞状态标志物的富集。同样，在apoAI（-/-）受体中没有观察到这些有益的变化，表明HDL的有益作用主要需要胆固醇逆向转运。总之，这些结果确立HDL作为小鼠动脉粥样硬化斑块中单核细胞衍生细胞的迁移和炎症特性的体内调节剂，并突出了这些细胞的表型可塑性。
HDL cholesterol (HDL-C) plasma levels are inversely related to cardiovascular disease risk. Previous studies have shown in animals and humans that HDL promotes regression of atherosclerosis. We hypothesized that this was related to an ability to promote the loss of monocyte-derived cells (CD68(+), primarily macrophages and macrophage foam cells) from plaques. To test this hypothesis, we used an established model of atherosclerosis regression in which plaque-bearing aortic arches from apolipoprotein E-deficient (apoE(-/-)) mice (low HDL-C, high non-HDL-C) were transplanted into recipient mice with differing levels of HDL-C and non-HDL-C: C57BL6 mice (normal HDL-C, low non-HDL-C), apoAI(-/-) mice (low HDL-C, low non-HDL-C), or apoE(-/-) mice transgenic for human apoAI (hAI/apoE(-/-); normal HDL-C, high non-HDL-C). Remarkably, despite persistent elevated non-HDL-C in hAI/apoE(-/-) recipients, plaque CD68(+) cell content decreased by > 50% by 1 wk after transplantation, whereas there was little change in apoAI(-/-) recipient mice despite hypolipidemia. The decreased content of plaque CD68(+) cells after HDL-C normalization was associated with their emigration and induction of their chemokine receptor CCR7. Furthermore, in CD68(+) cells laser-captured from the plaques, normalization of HDL-C led to decreased expression of inflammatory factors and enrichment of markers of the M2 (tissue repair) macrophage state. Again, none of these beneficial changes were observed in the apoAI(-/-) recipients, suggesting a major requirement for reverse cholesterol transport for the beneficial effects of HDL. Overall, these results establish HDL as a regulator in vivo of the migratory and inflammatory properties of monocyte-derived cells in mouse atherosclerotic plaques, and highlight the phenotypic plasticity of these cells.