Individual contributions of HDL-C, non-HDL-C, and apoE to atherosclerosis regression and to the migratory and inflammatory properties of plaque monocyte-derived (CD68+) cells

最近的发现增加了对动脉粥样硬化消退的理解，并鼓励了对其临床可行性的乐观态度。建立了一种新的小鼠动脉粥样硬化退化移植模型，将apoE缺陷小鼠（apoE-/-；人类动脉粥样硬化标准小鼠模型）的病变斑块含主动脉段放入正常血脂野生型（WT）受体中。一旦在WT环境中，病变主动脉段表现出一个消退过程，其特征是CD68+细胞（主要是巨噬细胞和泡沫细胞）通过诱导迁移过程显著而快速地损失。CD68+细胞的丢失依赖于趋化因子受体ccr72,3。除了获得迁移表型外，退化斑块CD68+细胞在M2抗炎状态标记物中也变得丰富，而在炎性M1巨噬细胞状态相关标记物中则减少。当斑块从apoE-/-转移到WT小鼠时，血浆环境有3个主要变化：1)高密度脂蛋白胆固醇（HDL- c）的正常化；2)降低非hdl - c；3) apoE升高。可以假设，每一种变化都有助于动脉粥样硬化的消退，即斑块CD68+细胞的损失，以及这些细胞中多种分子变化的调节。本研究的目的是确定HDL-C、非HDL-C和apoE对动脉粥样硬化消退以及斑块单核细胞来源（CD68+）细胞的迁移和炎症特性的个体贡献。这些研究与目前关于LDL-C和HDL-C对心血管疾病风险的相对重要性的临床争议以及斑块消退的新策略有关。

Recent discoveries have increased the understanding of atherosclerosis regression and have encouraged optimism about its clinical feasibility1. A novel transplant model of mouse atherosclerosis regression has been developed in which diseased plaque-containing aortic segments from apoE-deficient mice (apoE-/-; a standard mouse model of human atherosclerosis) were placed into normolipidemic wild type (WT) recipients. Once in the WT environment, diseased aortic segments displayed a regression process marked by remarkable and rapid loss of CD68+ cells (primarily macrophages and foam cells) through the induction of an emigration process. The loss of CD68+ cells was dependent on the chemokine receptor CCR72,3. In addition to acquiring a migratory phenotype, regressing plaque CD68+ cells also became enriched in markers of the M2 anti-inflammatory state and depleted in those associated with the inflammatory M1 macrophage state. There are 3 major changes in the plasma environment when plaques are transferred from apoE-/- to WT mice: 1) the normalization of HDL cholesterol (HDL-C); 2) the lowering of non-HDL-C; 3) and an increase of apoE. It can be hypothesized that each change contributes to atherosclerosis regression, as defined by a loss of plaque CD68+ cells, and to the regulation of multiple molecular changes in these cells. The goal of this study is to determine the individual contributions of HDL-C, non-HDL-C, and apoE to atherosclerosis regression and to the migratory and inflammatory properties of plaque monocyte-derived (CD68+) cells. These studies are relevant to the current clinical controversy on the relative importance of LDL-C and HDL-C to cardiovascular disease risk and to new strategies to regress plaques.