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了解，并鼓励了人们对其临床可行性的乐观1。建立了一种新的小鼠动脉粥样硬化消退移植模型，将apoE基因缺陷小鼠(apoE-/-；人类动脉粥样硬化的标准小鼠模型)中含有斑块的主动脉段移植到正常血脂野生型(WT)受体中。一旦进入WT环境，病变的主动脉节段就表现出一个退化的过程，其特点是CD68+细胞(主要是巨噬细胞和泡沫细胞)通过诱导迁移过程而显著而迅速地丧失。CD68+细胞的丢失依赖于趋化因子受体CCR72，3。除获得迁移表型外，退行性斑块中的CD68+细胞也变得富含M2抗炎状态的标志物，而与炎性M1巨噬细胞状态相关的标志物被耗尽。当斑块从apoE-/-转移到WT小鼠身上时，血浆环境有三个主要变化：1)高密度脂蛋白胆固醇(HDLc)正常化；2)非HDLc降低；3)apoE升高。可以假设，每个变化都有助于动脉粥样硬化的消退，其定义是斑块CD68+细胞的丢失，并对这些细胞中的多个分子变化进行调节。本研究的目的是确定高密度脂蛋白胆固醇、非高密度脂蛋白胆固醇和载脂蛋白E在动脉粥样硬化消退和斑块单核细胞衍生(CD68+)细胞的迁移和炎症特性中的单独作用。这些研究与目前关于低密度脂蛋白胆固醇和高密度脂蛋白胆固醇对心血管疾病风险的相对重要性的临床争议有关，也与消退斑块的新策略有关。

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.