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

HDL-C、非 HDL-C 和 apoE 对动脉粥样硬化消退以及斑块单核细胞衍生 (CD68) 细胞的迁移和炎症特性的个体贡献

• 批准号: 170683487
• 负责人: Dr. Bernd Hewing
• 金额: --
• 依托单位: Division of Cardiology
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2012-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/170683487?language=en
• 关键词: Individual; contributions; HDL; non; apoE

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.

最近的发现增加了对动脉粥样硬化消退的理解，并鼓励对其临床可行性持乐观态度1。已经开发了一种小鼠动脉粥样硬化消退的新型移植模型，其中将来自apoE缺陷小鼠（apoE-/-;人动脉粥样硬化的标准小鼠模型）的含有病变斑块的主动脉节段置于血脂正常的野生型（WT）受体中。一旦进入WT环境，病变主动脉节段显示出消退过程，其特征在于通过诱导迁移过程导致CD 68+细胞（主要是巨噬细胞和泡沫细胞）显著和快速损失。CD 68+细胞的损失依赖于趋化因子受体CCR 72，3。除了获得迁移表型外，消退斑块CD 68+细胞还富含M2抗炎状态的标志物，并耗尽与炎性M1巨噬细胞状态相关的标志物。当斑块从apoE-/-转移到WT小鼠时，血浆环境中有3个主要变化：1）HDL胆固醇（HDL-C）正常化; 2）非HDL-C降低; 3）apoE增加。可以假设，每种变化都有助于动脉粥样硬化消退，如斑块CD 68+细胞的损失所定义的，并且有助于调节这些细胞中的多种分子变化。 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和斑块单核细胞衍生（CD 68+）细胞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消退斑块的新策略相关。