AG1296 enhances plaque stability via inhibiting inflammatory responses and decreasing MMP-2 and MMP-9 expression in ApoE-/- mice
AG1296 enhances plaque stability via inhibiting inflammatory responses and decreasing MMP-2 and MMP-9 expression in ApoE-/- mice
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AG1296 通过抑制 ApoE-/- 小鼠的炎症反应并降低 MMP-2 和 MMP-9 表达来增强斑块稳定性
DOI：
10.1016/j.bbrc.2017.05.159
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发表时间：
2017-08-05
影响因子：
3.1
通讯作者：
Zheng, Lemin
中科院分区：
文献类型：
--
作者：
Dong, Min;Zhou, Changping;Zheng, Lemin
背景：动脉粥样硬化是一个进展为不稳定斑块的慢性过程。斑块破裂会导致急性冠脉综合征、血栓形成和中风等有害后果。 AG1296 是一种有效的酪氨酸激酶抑制剂，能够阻断 PDGF-PDGFR 信号通路。本研究旨在评估AG1296对斑块稳定性的影响并探讨其潜在机制。方法：通过血管周围项圈放置在ApoE -/- 小鼠颈动脉中诱导动脉粥样硬化斑块。所有小鼠随机分为PBS组和AG1296组。术后3周，采集颈动脉进行组织学分析。结果：AG1296组斑块面积减少41.5%（p=0.0041），巨噬细胞和脂质含量分别减少43.5%（p=0.0003）和35.6%（p=0.0032）。 AG1296组平滑肌细胞含量增加22.3%（p = 0.0214）。脆弱指数下降了 483% (p = 0.0002)。 AG1296 组炎症因子 IL-6 和 TNF-α 分别降低 49.0% (p = 0.0008) 和 51.8% (p < 0.0001)，基质金属蛋白酶 MMP-2 和 MMP-9 分别降低 54.1% (p = 0.0004) 和 37.1% (p < 0.0001)。 AG1296 组 M1 巨噬细胞标志物 (MCP-1) 下调 30.3% (p = 0.0007)，M2 巨噬细胞标志物 (ARG-1) 增加 55.2% (p = 0.0009)。结论：AG1296 通过抑制炎症反应、减少基质金属蛋白酶的表达和促进动脉粥样硬化斑块的稳定性，从而抑制动脉粥样硬化斑块进展并增强斑块稳定性。巨噬细胞从促炎表型转变为抗炎表型。 (C) 2017 Elsevier Inc. 保留所有权利。
Background: Atherosclerosis is a chronic process that progresses to unstable plaques. Plaque rupture leads to deleterious consequences such as acute coronary syndrome, thrombosis and stroke. AG1296 is a potent tyrosine kinase inhibitor which is able to block PDGF-PDGFR signaling pathway. This study aims to assess the effect of AG1296 on plaque stability and explore the potential mechanisms.Methods: Atherosclerotic plaques were induced in carotid arteries in ApoE -/- mice by perivascular collar placement. All mice were randomly divided into PBS and AG1296 groups. 3 weeks after the surgery, the carotid arteries were harvested for histological analysis.Results: In AG1296 group, plaque area decreased by 41.5% (p = 0.0041) and the contents of macrophages and lipids decreased by 43.5% (p = 0.0003) and 35.6% (p = 0.0032) respectively. The contents of smooth muscle cells increased by 22.3% (p = 0.0214) in AG1296 group. Vulnerable index decreased by 483% (p = 0.0002). The inflammation factors IL-6 and TNF- alpha decreased by 49.0% (p = 0.0008) and 51.8% (p < 0.0001) and matrix metalloproteinases MMP-2 and MMP-9 decreased by 54.1% (p = 0.0004) and 37.1% (p < 0.0001) in AG1296 group. M1 macrophage markers (MCP-1) were downregulated by 30.3% (p = 0.0007) and M2 macrophage markers (ARG-1) were increased by 55.2% (p = 0.0009) in AG1296 group.Conclusion: AG1296 inhibited the atherosclerotic plaque progression and enhanced plaque stability by inhibiting inflammatory responses, reducing the expression of matrix metalloproteinases and promoting macrophages from proinflammatory phenotype to anti-inflammatory phenotype. (C) 2017 Elsevier Inc. All rights reserved.