Selumetinib promotes coronary collateral circulation by inducing M2-like macrophage polarization following myocardial infarction

被引:0
|
作者
Lin, Ke-chuan [1 ]
He, Wei [2 ,3 ,4 ]
Wang, Dan [2 ]
Yao, Mei-lian [3 ]
Chen, Jing [3 ]
Chen, Mei-fang [2 ,3 ,4 ]
Zhang, Guo-gang [1 ,4 ]
Li, Chuan-chang [2 ,3 ,4 ]
Zhu, Ling-ping [2 ,3 ,4 ]
Bai, Yong-ping [2 ,3 ,4 ,5 ]
机构
[1] Cent South Univ, Dept Cardiol, Xiangya Hosp 3, Changsha 410013, Peoples R China
[2] Cent South Univ, Xiangya Hosp, Dept Geriatr Med, Changsha 410008, Peoples R China
[3] Cent South Univ, Xiangya Hosp, Ctr Coronary Circulat, Changsha 410008, Peoples R China
[4] Cent South Univ, Xiangya Hosp, Natl Clin Res Ctr Geriatr Disorders, Changsha 410008, Peoples R China
[5] Cent South Univ, Dept Cardiol, Xiangya Hosp, Changsha 410013, Peoples R China
来源
ACTA PHARMACOLOGICA SINICA | 2025年
基金
中国国家自然科学基金;
关键词
myocardial infarction; coronary collateral circulation; selumetinib; M2-like macrophage polarization; RIT1/MAPK/ERK1/2 signaling pathway;
D O I
10.1038/s41401-025-01508-8
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
Coronary collateral circulation (CCC) construction could be a practical therapeutic strategy for patients following myocardial infarction (MI), yet effective therapeutic drugs remain scarce. In this study we conducted database federation analyses to identify FDA-approved drugs that could promote CCC after MI injury. By comparing the differentially expressed genes in peripheral blood mononuclear cells (PBMCs) from two public gene profiles: one comparing patients with good versus poor CCC, and another with good versus poor heart function, the overlapped genes were analyzed using CMap, a popular resource designed for FDA approved drug. As a result, selumetinib emerged as a potential therapeutic drug to facilitate CCC formation. In MI mouse model induced by permanent ligation of left anterior descending (LAD) coronary artery, administration of selumetinib (2.5 mg/kg, i.p.) at the indicated time-points significantly enhanced CCC by promoting the polarization of macrophages from the pro-inflammatory M1-like phenotype to the pro-angiogenic M2-like phenotype, which was confirmed by 3D visualization through micro-CT imaging and immunofluorescent staining. We demonstrated that selumetinib (5 mu M) promoted THP-1 differentiated into M2-like phenotype in vitro, and increased VEGFA secretion. Selumetinib-treated macrophages significantly enhanced in vitro angiogenesis of HUVECs in cocultured assay. We found that selumetinib (2.5 and 5 mu M) dose-dependently inhibited the expression of the RIT1 in THP-1 derived M1 macrophage; knockdown of RIT1 significantly polarized M2-like phenotype via the MAPK/ERK1/2 signaling pathway, which was equal to the efficiency of selumetinib. In rescued experiments, specific overexpression of RIT1 in macrophage by injecting with targeting F4/80 promoter AAV9 in mice, could block the M2-like phenotype shifts and CCC formation by selumetinib. Finally, honokiol, a MAPK/ERK1/2 agonist was able to reverse the effects of selumetinib on CCC in mice with MI. In conclusion, selumetinib possesses therapeutic potential for induction of CCC formation after MI.
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页数:15
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