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

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.