AG1296 enhances plaque stability via inhibiting inflammatory responses and decreasing MMP-2 and MMP-9 expression in ApoE-/- mice.

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.