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The regression of atherosclerosis: Molecular insights from novel mouse models.

机译：动脉粥样硬化的回归：新型小鼠模型的分子见解。

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摘要

Atherosclerosis is the leading underlying cause of death in the developed world. We have developed a transplantation-based mouse model of atherosclerosis regression by allowing plaques to form in a model of human atherosclerosis, the apoE-deficient (apoE-/-) mouse, and then placing them into a recipient mouse with a normolipidemic plasma environment. In this model, we reported emigration of plaque cells filled with cholesterol (macrophage foam cells) to regional and systemic lymph nodes after three days in the normolipidemic (regression) environment. Experimentation revealed that under regression conditions, emigration required the expression of the chemokine receptor CCR7 on the macrophage foam cells. Importantly, we discovered that both LXRalpha and LXRbeta, nuclear hormone receptors that play key roles in maintaining cholesterol homeostasis in macrophages, are required for maximal CCR7 gene expression and macrophage foam cell depletion and migration out of plaques in vivo. Given the strong inverse correlation between plasma HDL and the risk of cardiovascular disease, we next wondered whether HDL was a regression factor. Interestingly, we found that the restoration in apoE-/- mice of a naturally low plasma HDL to normal levels, despite persistent hyperlipidemia, can promote macrophage foam cell depletion and migration. Surprisingly, deficiency of HDL, despite normolipidemia, impaired macrophage foam cell depletion and migration. Furthermore, the HDL deficiency was associated with diminished CCR7 expression in macrophage foam cells and decreased expression of markers of the M2 (anti-inflammatory) macrophage state, whereas the opposite pattern was seen in mice with the restored HDL levels. In order to assess whether any of our observations was reflective of the regression process itself, and not model specific, we studied a non-transplant mouse model of regression (the "Reversa" mouse) and found that indeed key features of regression- the induction of CCR7 expression in macrophage foam cells, the migration of these cells out of the plaque, and their skewing towards the M2-like state- were also observed in this model. Further study at the molecular level is hoped to lead to the identification of critical pathways that can be manipulated to develop new therapies to promote the regression of atherosclerosis.
机译：动脉粥样硬化是发达国家的主要潜在死亡原因。通过允许斑块在人类动脉粥样硬化模型中形成apoE缺陷型（apoE-/-）小鼠，然后将它们放入具有血脂正常血浆环境的受体小鼠中，我们已经开发了基于移植的动脉粥样硬化回归模型。在该模型中，我们报道了在降血脂（回归）环境中三天后，充满胆固醇的噬菌斑细胞（巨噬细胞泡沫细胞）迁移到区域和全身淋巴结。实验表明，在回归条件下，迁移需要在巨噬细胞泡沫细胞上表达趋化因子受体CCR7。重要的是，我们发现LCCRα和LXRβ这两种在维持巨噬细胞胆固醇稳态中起关键作用的核激素受体，对于最大的CCR7基因表达和巨噬细胞泡沫细胞耗竭以及体内斑块的迁移都是必需的。鉴于血浆HDL与心血管疾病的风险之间存在强烈的逆相关性，我们接下来想知道HDL是否是一种回归因素。有趣的是，我们发现，尽管持续存在高脂血症，但在apoE-/-小鼠中自然低血浆HDL恢复至正常水平仍可以促进巨噬细胞泡沫细胞的耗竭和迁移。出乎意料的是，尽管血脂异常，但HDL缺乏会损害巨噬细胞泡沫细胞的耗竭和迁移。此外，HDL缺乏与巨噬细胞泡沫细胞中CCR7表达减少和M2（抗炎）巨噬细胞状态标志物表达降低有关，而在HDL恢复水平的小鼠中观察到相反的模式。为了评估我们的观察结果是否反映了回归过程本身，而不是特定于模型，我们研究了回归的非移植小鼠回归模型（“ Reversa”小鼠），发现回归的关键特征确实在于在该模型中还观察到了巨噬细胞泡沫细胞中CCR7表达的改变，这些细胞从斑块中迁移出来以及它们向M2样状态的倾斜。希望在分子水平上进行进一步的研究，以导致确定关键途径，可以操纵这些关键途径来开发新的疗法以促进动脉粥样硬化的消退。

著录项

  • 作者

    Feig, Jonathan E.;

  • 作者单位

    New York University.;

  • 授予单位 New York University.;
  • 学科 Biology Cell.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 249 p.
  • 总页数 249
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

  • 入库时间 2022-08-17 11:38:25

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