The Leon H. Charney Division of Cardiology, Department of Medicine, The Marc and Ruti Bell Program in Vascular Biology, New York University School of Medicine, New York, NY 10016, USA.
Proc Natl Acad Sci U S A. 2011 Apr 26;108(17):7166-71. doi: 10.1073/pnas.1016086108. Epub 2011 Apr 11.
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.
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 可促进动脉粥样硬化的消退。我们假设这与促进斑块中单核细胞来源的细胞（CD68（+），主要为巨噬细胞和泡沫巨噬细胞）丢失的能力有关。为了验证这一假设，我们使用了一种已建立的动脉粥样硬化消退模型，其中载脂蛋白 E 缺乏（apoE（-/-））小鼠的载脂蛋白 E 缺乏（apoE（-/-））小鼠（低 HDL-C，高非 HDL-C）的主动脉弓斑块被移植到具有不同 HDL-C 和非 HDL-C 水平的受体小鼠中：C57BL6 小鼠（正常 HDL-C，低非 HDL-C），apoAI（-/-）小鼠（低 HDL-C，低非 HDL-C）或载脂蛋白 AI（apoAI）转基因 apoE（-/-）小鼠（正常 HDL-C，高非 HDL-C）。值得注意的是，尽管 hAI/apoE（-/-）受体中的非 HDL-C 持续升高，但在移植后 1 周，斑块 CD68（+）细胞含量减少了> 50％，而 apoAI（-/-）受体小鼠的变化很小，尽管存在脂质减少。 HDL-C 正常化后斑块 CD68（+）细胞含量减少与它们的迁移和趋化因子受体 CCR7 的诱导有关。此外，在从斑块中激光捕获的 CD68（+）细胞中，HDL-C 的正常化导致炎症因子的表达减少和 M2（组织修复）巨噬细胞状态标志物的富集。同样，在 apoAI（-/-）受体中未观察到这些有益变化，这表明胆固醇逆转运对 HDL 的有益作用有主要要求。总体而言，这些结果确立了 HDL 作为体内调节小鼠动脉粥样硬化斑块中单核细胞来源细胞的迁移和炎症特性的调节剂，并强调了这些细胞的表型可塑性。
