曲古抑菌素C通过上调Krüppel样转录因子2抑制TNFα诱导的内皮细胞炎症

Trichostatin C attenuates TNFα-induced inflammation in endothelial cells by up-regulating Krüppel-like factor 2

Krüppel样转录因子2(Krüppel-like factor 2,KLF2)在内皮细胞炎症、血栓形成、血管生成以及巨噬细胞的炎症和极化等过程中发挥调节作用,上调KLF2的表达具有防治动脉粥样硬化的潜力。本研究利用KLF2表达上调剂筛选模型,从一株链霉菌CPCC 203909的大米发酵次级代谢产物中分离得到一个KLF2小分子上调剂曲古抑菌素C(trichostatin C,TSC)。TSC可以显著抑制肿瘤坏死因子α(tumor necrosis factorα,TNFα)诱导的单核细胞(THP-1)黏附到人脐静脉内皮细胞(human umbilical vein endothelial cells,HUVECs)上;Western blot实验结果表明,TSC具有抑制血管细胞黏附分子-1(vascular cell adhesion molecule-1,VCAM-1)的作用,从而减轻内皮细胞炎症;过表达组蛋白去乙酰化酶(histone deacetylase,HDAC)质粒转染和分子对接实验结果表明,TSC通过抑制HDAC 4/5/7来上调KLF2的表达。综上,TSC通过抑制HDAC 4/5/7上调KLF2的表达从而减轻TNFα诱导的内皮细胞炎症,具有预防和治疗动脉粥样硬化的潜力。

Krüppel-like transcription factor 2(KLF2)plays a key regulatory role in endothelial inflammation,thrombosis,angiogenesis and macrophage inflammation and polarization,and up-regulation of KLF2 expression has the potential to prevent and treatment atherosclerosis.In this study,trichostatin C(TSC)was obtained from the secondary metabolites of rice fermentation of Streptomyces sp.CPCC 203909 as a KLF2 up-regulator by using a high throughput screening model based on a KLF2 promoter luciferase reporter assay.TSC significantly inhibited the adhesion of tumor necrosis factor-α(TNFα)induced monocytes(THP-1)to human umbilical vein endothelial cells(HUVECs).Western blot results showed that TSC decreased TNFαinduced the protein expression increase of vascular cell adhesion molecule-1(VCAM-1),and thereby inhibited endothelial inflammation.The results of histone deacetylase(HDAC)overexpression and molecular docking experiments showed that TSC upregulated the expression of KLF2 by inhibiting subtypes of HDAC 4/5/7.In conclusion,this study suggests that TSC up-regulates the expression of KLF2 through inhibiting HDAC 4/5/7 and thus inhibits TNFαinduced endothelial inflammation,and it has the potential to prevent and treat atherosclerosis.