载脂蛋白 E 基因敲除小鼠中内脂素诱导的炎症反应在动脉粥样硬化进展中的作用

Impaired infarct healing in atherosclerotic mice with Ly-6C(hi) monocytosis.

机构信息

Center for Systems Biology, Simches Research Building, Massachusetts General Hospital and Harvard Medical School Boston, Massachusetts 02114, USA.

出版信息

J Am Coll Cardiol. 2010 Apr 13;55(15):1629-38. doi: 10.1016/j.jacc.2009.08.089.

DOI:10.1016/j.jacc.2009.08.089

PMID:20378083

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2852892/

Abstract

OBJECTIVES

The aim of this study was to test whether blood monocytosis in mice with atherosclerosis affects infarct healing.

BACKGROUND

Monocytes are cellular protagonists of tissue repair, and their specific subtypes regulate the healing program after myocardial infarction (MI). Inflammatory Ly-6C(hi) monocytes dominate on Day 1 to Day 4 and digest damaged tissue; reparative Ly-6C(lo) monocytes dominate on Day 5 to Day 10 and promote angiogenesis and scar formation. However, the monocyte repertoire is disturbed in atherosclerotic mice: Ly-6C(hi) monocytes expand selectively, which might disrupt the resolution of inflammation.

METHODS

Ex vivo analysis of infarcts included flow cytometric monocyte enumeration, immunoactive staining, and quantitative polymerase chain reaction. To relate inflammatory activity to left ventricular remodeling, we used a combination of noninvasive fluorescence molecular tomography (FMT-CT) and physiologic imaging (magnetic resonance imaging).

RESULTS

Five-day-old infarcts showed >10x more Ly-6C(hi) monocytes in atherosclerotic (apoE(-/-)) mice compared with wild-type mice. The injured tissue in apoE(-/-) mice also showed a more pronounced inflammatory gene expression profile (e.g., increased tumor necrosis factor-alpha and myeloperoxidase and decreased transforming growth factor-beta) and a higher abundance of proteases, which are associated with the activity of Ly-6C(hi) monocytes. The FMT-CT on Day 5 after MI showed higher proteolysis and phagocytosis in infarcts of atherosclerotic mice. Serial magnetic resonance imaging showed accelerated deterioration of ejection fraction between Day 1 and Day 21 after MI in apoE(-/-). Finally, we could recapitulate these features in wild-type mice with artificially induced Ly-6C(hi) monocytosis.

CONCLUSIONS

Ly-6C(hi) monocytosis disturbs resolution of inflammation in murine infarcts and consequently enhances left ventricular remodeling. These findings position monocyte subsets as potential therapeutic targets to augment tissue repair after infarction and to prevent post-MI heart failure.

摘要

目的

本研究旨在测试动脉粥样硬化小鼠血液中的单核细胞增多是否会影响梗死愈合。

背景

单核细胞是组织修复的细胞主角，其特定亚型调节心肌梗死（MI）后的愈合程序。炎症性 Ly-6C(hi)单核细胞在第 1 天至第 4 天占主导地位，消化受损组织；修复性 Ly-6C(lo)单核细胞在第 5 天至第 10 天占主导地位，促进血管生成和瘢痕形成。然而，动脉粥样硬化小鼠的单核细胞谱受到干扰：Ly-6C(hi)单核细胞选择性扩增，这可能破坏炎症的消退。

方法

对梗死进行离体分析，包括流式细胞术单核细胞计数、免疫活性染色和定量聚合酶链反应。为了将炎症活性与左心室重构相关联，我们使用非侵入性荧光分子断层扫描（FMT-CT）和生理成像（磁共振成像）相结合的方法。

结果

与野生型小鼠相比，5 天大的梗死在动脉粥样硬化（apoE(-/-)）小鼠中 Ly-6C(hi)单核细胞多 10 倍以上。apoE(-/-)小鼠受伤组织也表现出更明显的炎症基因表达谱（例如，肿瘤坏死因子-α和髓过氧化物酶增加，转化生长因子-β减少）和更高丰度的蛋白酶，这些与 Ly-6C(hi)单核细胞的活性有关。MI 后第 5 天的 FMT-CT 显示，动脉粥样硬化小鼠的梗死中蛋白酶解和吞噬作用更高。连续磁共振成像显示，在 MI 后第 1 天至第 21 天，apoE(-/-)小鼠的射血分数恶化更快。最后，我们可以在通过人工诱导 Ly-6C(hi)单核细胞增多的野生型小鼠中重现这些特征。