ArticleActa pharmacologica Sinica2025
Selumetinib promotes coronary collateral circulation by inducing M2-like macrophage polarization following myocardial infarction.
Article in Acta pharmacologica Sinica, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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10 authors.
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Abstract
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 μM) 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 μM) 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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