1. Academic Validation
  2. 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

  • Biochem Biophys Res Commun. 2017 Aug 5;489(4):426-431. doi: 10.1016/j.bbrc.2017.05.159.
Min Dong 1 Changping Zhou 1 Liang Ji 1 Bing Pan 2 Lemin Zheng 3
Affiliations

Affiliations

  • 1 The Institute of Cardiovascular Sciences and Institute of Systems Biomedicine, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Sciences of Ministry of Education, Health Science Center, Peking University, Beijing 100191, China.
  • 2 The Institute of Cardiovascular Sciences and Institute of Systems Biomedicine, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Sciences of Ministry of Education, Health Science Center, Peking University, Beijing 100191, China. Electronic address: panbintz@163.com.
  • 3 The Institute of Cardiovascular Sciences and Institute of Systems Biomedicine, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Sciences of Ministry of Education, Health Science Center, Peking University, Beijing 100191, China. Electronic address: zhengl@bjmu.edu.cn.
Abstract

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 48.3% (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.

Keywords

Atherosclerosis; Inflammation; Matrix metalloproteinases; Plaque stability.

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