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 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.