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

作　　者：雷丽娟 陈明华 李迎红 姜新海 王伟志 赵丽萍 王晨吟 陈渝川 张语嫣 巫晔翔 李顺旺 韩江雪 李依宁 盛任 张煜皓 张晶 余利岩 司书毅 许艳妮 LEI Li-juan;CHEN Ming-hua;LI Ying-hong;JIANG Xin-hai;WANG Wei-zhi;ZHAO Li-ping;WANG Chen-yin;CHEN Yu-chuan;ZHANG Yu-yan;WU Ye-xiang;LI Shun-wang;HAN Jiang-xue;LI Yi-ning;SHENG Ren;ZHANG Yu-hao;ZHANG Jing;YU Li-yan;SI Shu-yi;XU Yan-ni(NHC Key Laboratory of Biotechnology of Antibiotics,National Center for Screening Novel Microbial Drugs,Institute of Medicinal Biotechnology,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050,China)

机构地区：[1]中国医学科学院、北京协和医学院医药生物技术研究所,国家新药(微生物)筛选实验室,国家卫生健康委员会抗生素生物工程重点实验室,北京100050

出　　处：《药学学报》2023年第8期2375-2383,共9页Acta Pharmaceutica Sinica

基　　金：中国医学科学院医学与健康科技创新工程项目(2022-JKCS-10,2019-RC-HL-009,2021-1-I2M-030);京津冀基础研究合作专项(19JCZD‐JC63900);国家自然科学基金面上资助项目(81973328)。

摘　　要：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.

关 键 词：曲古抑菌素C Krüppel样转录因子2 内皮细胞炎症 动脉粥样硬化 血管细胞黏附分子-1 组蛋白去乙酰化酶 

分 类 号：R966[医药卫生—药理学]