Institute of Biomedicine, University of Turku, Kiinamyllynkatu 10, 20014, Turku, Finland.
Turku Doctoral Programme of Molecular Medicine, University of Turku, Turku, Finland.
Sci Rep. 2021 Aug 17;11(1):16661. doi: 10.1038/s41598-021-96033-z.
The return of blood flow to ischemic heart after myocardial infarction causes ischemia-reperfusion injury. There is a clinical need for novel therapeutic targets to treat myocardial ischemia-reperfusion injury. Here we screened for targets for the treatment of ischemia-reperfusion injury using a combination of shRNA and drug library analyses in HL-1 mouse cardiomyocytes subjected to hypoxia and reoxygenation. The shRNA library included lentiviral constructs targeting 4625 genes and the drug library 689 chemical compounds approved by the Food and Drug Administration (FDA). Data were analyzed using protein-protein interaction and pathway analyses. EGFR inhibition was identified as a cardioprotective mechanism in both approaches. Inhibition of EGFR kinase activity with gefitinib improved cardiomyocyte viability in vitro. In addition, gefitinib preserved cardiac contractility in zebrafish embryos exposed to hypoxia-reoxygenation in vivo. These findings indicate that the EGFR inhibitor gefitinib is a potential candidate for further studies of repurposing the drug for the treatment of myocardial infarction.
心肌梗死后缺血心肌血流的恢复会导致缺血再灌注损伤。因此，临床需要寻找新的治疗靶点来治疗心肌缺血再灌注损伤。在这里，我们通过对缺氧/复氧 HL-1 小鼠心肌细胞进行 shRNA 和药物文库分析的组合筛选，找到了针对这种损伤的治疗靶点。shRNA 文库包含靶向 4625 个基因的慢病毒构建体，而药物文库则包含了 FDA 批准的 689 种化学化合物。我们使用蛋白质-蛋白质相互作用和通路分析对数据进行了分析。结果表明，EGFR 抑制是这两种方法中的一种心脏保护机制。用吉非替尼抑制 EGFR 激酶活性可提高体外心肌细胞活力。此外，吉非替尼还能在体内缺氧/复氧暴露的斑马鱼胚胎中保持心脏收缩力。这些发现表明，EGFR 抑制剂吉非替尼可能是进一步研究该药物用于治疗心肌梗死的候选药物。
