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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

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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 ^*

药学学报 | 研究论文 2023,58(8): 2375-2383

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药学学报 |研究论文 2023 , 58 (8) : 2375 -2383

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

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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^*

作者信息

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

通讯作者:

*余利岩, Tel: 86-10-63187118, E-mail: yly@cpcc.ac.cn;

司书毅, Tel: 86-10-63180604, E-mail: sisyimb@hotmail.com;

许艳妮, Tel: 86-10-63180623, E-mail: xuyanniwendeng@hotmail.com

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

Affiliations

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

出版时间: 2023-08-12 doi: 10.16438/j.0513-4870.2022-1406

文章导航

摘要

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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 factor α, 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。

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

Abstract

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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 TNFα induced 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 TNFα induced endothelial inflammation, and it has the potential to prevent and treat atherosclerosis.

Key words

trichostatin C / Krüppel-like factor 2 / endothelial inflammation / atherosclerosis / vascular cell adhesion molecule-1 / histone deacetylase

引用本文

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. 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. 药学学报, 2023 , 58 (8) : 2375 -2383 . DOI: 10.16438/j.0513-4870.2022-1406

Li-juan LEI, Ming-hua CHEN, Ying-hong LI, Xin-hai JIANG, Wei-zhi WANG, Li-ping ZHAO, Chen-yin WANG, Yu-chuan CHEN, Yu-yan ZHANG, Ye-xiang WU, Shun-wang LI, Jiang-xue HAN, Yi-ning LI, Ren SHENG, Yu-hao ZHANG, Jing ZHANG, Li-yan YU, Shu-yi SI, Yan-ni XU. Trichostatin C attenuates TNFα-induced inflammation in endothelial cells by up-regulating Krüppel-like factor 2[J]. Acta Pharmaceutica Sinica, 2023 , 58 (8) : 2375 -2383 . DOI: 10.16438/j.0513-4870.2022-1406

正文

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心血管疾病(cardiovascular disease, CVD) 是全球范围内引起死亡的主要原因^{[1, 2]}, 在中国城乡居民疾病死亡构成比中占首位, 并且CVD患病率在我国处于持续上升阶段^[3]。动脉粥样硬化(atherosclerosis, AS) 是一种慢性血管炎症性疾病, 是CVD的病理基础^{[4, 5]}。内皮细胞炎症在动脉粥样硬化的发生发展中起着重要作用, 肿瘤坏死因子α (tumor necrosis factor α, TNFα) 等刺激可诱导内皮细胞炎症, 内皮细胞表面表达血管细胞黏附分子-1 (vascular cell adhesion molecule-1, VCAM-1) 和细胞间黏附分子-1 (intercellular adhesion molecule-1, ICAM-1), VCAM-1和ICAM-1表达增加促进了单核细胞的黏附以及迁移到内皮下血管间隙, 单核细胞吞噬内化修饰的脂蛋白后最终变成泡沫细胞, 促进斑块的发展^[6-8]。

Krüppel样转录因子2 (Krüppel-like factor 2, KLF2) 是一种由层流剪切应力诱导的DNA结合转录因子^{[9, 10]}, 有研究发现klf2杂合子小鼠的动脉粥样硬化斑块面积显著增加^[11]。KLF2可以增加内皮细胞中内皮型一氧化氮合酶(endothelial nitric oxide synthase, eNOS)、一氧化氮(nitrogen monoxide, NO)、血栓调节素(thrombomodulin, TM) 的表达, 抑制VCAM-1、ICAM-1、白介素-1β、核因子κB等的表达。此外, 他汀类降血脂药物可以通过上调KLF2的表达而发挥抗动脉粥样硬化作用^[12]。因此, KLF2是内皮细胞中一个有前景的抗动脉粥样硬化靶点^{[13, 14]}, 筛选能够上调KLF2的小分子化合物并研究其抑制内皮细胞炎症的药理作用及机制, 对于防治动脉粥样硬化等CVD有着重要意义。

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小分子化合物曲古抑菌素C (trichostatin C, TSC), 其能显著上调KLF2的表达, 有效减少TNFα诱导的单核细胞黏附和VCAM-1的表达, 从而抑制内皮细胞炎症, 具有抗动脉粥样硬化的前景。

材料与方法

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主要仪器 链霉菌CPCC 203909保藏于中国医学科学院医药生物技术研究所中国药学微生物菌种保藏管理中心; 恒温摇床(上海捷呈实验仪器有限公司); HPX-9162MBE恒温培养箱(亚速旺上海商贸有限公司); BXM-30R蒸汽灭菌锅(上海化科实业有限公司); KQ5200E超声清洗机(昆山市超声仪器有限公司); DLSB-20低温冷却循环泵(郑州长城科工贸有限公司); SHZ-B-Ⅲ循环水式真空泵(郑州恒岩仪器有限公司); Agilent 1200分析型高效液相色谱、Agilent LC-MSD-Trap/SL1100系列液相色谱-质谱联用仪(美国Agilent公司); Waters G2-XS Q-TOF质谱仪(美国Waters公司); Shimadzu 20AT分析型高效液相色谱仪、Shimadzu SPD-M20A型紫外检测器(日本Shimadzu公司); 核磁共振波谱仪Bruker AVⅢHD-600MHz (美国Bruker公司); 中压快速制备色谱仪Flash RF150 (环球香港科技有限公司); 反相分析色谱柱Capcell Pak AQ (5 μm, 4.6 mm × 150 mm) (日本资生堂公司); 反相半制备色谱柱(X Charge C18 10 μm, 10 mm × 250 mm) (华谱科仪科技有限公司); 二氧化碳(CO₂) 恒温细胞培养箱(美国Thermo Fisher Scientific公司); FTC-3000实时荧光定量PCR仪(加拿大Funglyn Biotech公司); EnVision多功能酶标仪(美国Perkin Elmer公司)。

主要试剂 ISP medium 2培养基(美国Becton, Dickinson公司); DMEM高糖培养基、RPMI 1640培养基、BCA法蛋白浓度测定试剂盒、Lipofectamine 2000脂质体来源于美国Thermo Fisher Scientific公司; 内皮细胞培养基来源于美国ScienCell公司; 胎牛血清(fetal bovine serum, FBS) 来源于美国Gibco公司; 细胞增殖毒性检测试剂盒(CCK-8)、RIPA (radio immunoprecipitation assay) 细胞裂解液购买于普利莱基因技术有限公司; 重组人TNFα来源于美国R & D Systems公司; VCAM-1一抗购买于英国Abcam公司; ICAM-1一抗购买于美国Cell Signaling Technology公司; 山羊抗兔、山羊抗鼠的二抗购自北京中杉金桥生物技术有限公司; 增强型HRP底物化学发光液(ECL) 购自美国Millipore公司; RNA提取试剂盒QIAGEN RNeasy Mini kit购买于德国Qiagen公司; cDNA反转录试剂盒购买于北京全式金生物技术有限公司; RNA荧光定量试剂盒FastStart Universal SYBR Green Master Mix购自瑞士Roche公司; 荧光素酶检测试剂盒购自南京诺唯赞生物科技股份有限公司; 组蛋白去乙酰化酶(histone deacetylase, HDAC) 质粒(带Flag标签) (HDAC1, #13820; HDAC2, #36830; HDAC3, #13819; HDAC4, #13821; HDAC5, #13822; HDAC6, #13823; HDAC7, #13824; HDAC8, #13825) 购买于美国Addgene公司。

菌株发酵 在28 ℃条件下, 把链霉菌CPCC 203909接种于ISP medium 2 (0.4%酵母膏、1.0%麦芽膏、0.4%右旋糖和2.0%琼脂) 斜面培养基上, 复苏的菌株培养2天后接种到含有已灭菌100 mL A2液体培养基(1.0%葡萄糖、3.0%可溶性淀粉、2.0%棉籽粉、0.3%酵母膏、0.3%硫酸铵、0.1%硫酸镁、0.1%磷酸氢二钾、0.1%氯化钠和0.5%碳酸钙) 的500 mL三角瓶内, 在180 r·min^-1、28 ℃的摇床内培养2天后将其作为种子液。250袋培养袋内含有50 g大米和50 mL去离子水, 封口后用高压灭菌锅进行灭菌(121 ℃, 30 min), 待大米培养基冷却后, 在超净台中每袋培养基加入5 mL种子液, 28 ℃培养箱中培养30天。

分离纯化 将链霉菌CPCC 203909发酵结束后的大米发酵物用95%乙醇超声提取2次, 将提取液过滤后进行减压浓缩, 得到粗提物的混悬水溶液, 然后用乙酸乙酯萃取3次, 将萃取液减压浓缩后得到111.36 g粗浸膏。将粗浸膏进行硅胶柱层析, 二氯甲烷-甲醇梯度(1∶0~0∶1, v/v) 进行第一次的分离, 甲醇洗脱部分得到4个组分(A~D)。A组分用闪式C18柱分离, 以35%乙腈(含有0.1%三氟醋酸) 流动相洗脱, 分成4个亚组分(A1~A4)。A3经半制备高效液相色谱(X Charge C18, 10 mm × 250 mm; 35% 乙腈-含0.1%三氟醋酸的水等度洗脱; 1 mL·min^-1) 制备得化合物TSC (8.62 mg)。TSC的结构经紫外检测器、核磁共振波谱仪、液相色谱-质谱联用仪进行鉴别与确定。

细胞培养 非洲绿猴SV40转化的肾细胞(COS-7) 由实验室前期保存^{[15, 16]}, 培养于含10% FBS的DMEM培养基中; 人脐静脉内皮细胞(human umbilical vein endothelial cells, HUVECs) 购买于德国PromoCell公司, 培养于内皮细胞培养基(#34823, ScienCell公司), 6代以内的HUVECs用于实验; 人急性单核细胞白血病细胞(THP-1) 购买于中国医学科学院基础医学研究所细胞资源中心, 培养于含10% FBS的RPMI 1640培养基。所有的细胞均于37 ℃、5% CO₂的细胞培养箱中培养。

细胞活力检测 将处于对数生长期的HUVECs接种于96孔细胞培养板中, 待细胞贴壁后吸弃原有培养基, 加入含有不同浓度TSC的培养基(0、1.0、2.5、5.0、10、20和40 μmol·L^-1), 37 ℃培养24 h后, 每孔加入10 μL CCK-8后在37 ℃培养2 h, 检测其在450 nm波长处的吸光值。

单核细胞黏附实验 将HUVECs接种于6孔细胞培养板中, 不同浓度TSC (0、0.1、1.0、5.0和10 μmol·L^-1) 处理18 h后, 10 ng·mL^-1 TNFα加入培养基中继续刺激6 h。然后加入0.5 mL THP-1细胞(细胞密度为每毫升4×10⁶个) 继续孵育30 min。用不含FBS的RPMI 1640培养基轻轻漂洗3次以移除未黏附在HUVECs上的THP-1细胞。显微镜拍照后对HUVECs上黏附的THP-1细胞数量进行定量。

蛋白印迹分析 RIPA裂解液裂解细胞后提取细胞中总蛋白, BCA检测试剂盒测定细胞中蛋白浓度并将其定量到相同浓度。将制备好的蛋白样品利用SDS-PAGE电泳进行分离, 然后利用湿转法的步骤将蛋白转移到聚偏二氟乙烯膜(PVDF) 上, 5%脱脂牛奶封闭1 h, 孵育相应的一抗4 ℃摇床过夜, TBST漂洗3次, 每次10 min。孵育相应的二抗, 室温1 h, TBST漂洗3次, 使用蛋白发光液在Tanon 5200全自动化学发光图像分析系统成像。用Image J软件对蛋白条带进行扫描定量。

实时定量聚合酶链式反应(real-time quantitative polymerase chain reaction, RT-qPCR) 不同浓度的TSC (0、0.1、1.0、5.0和10 μmol·L^-1) 处理HUVECs 24 h后收集细胞。用QIAGEN RNeasy试剂盒提取细胞中的总RNA, 利用cDNA反转录试剂盒将提取的RNA反转录为cDNA, -20 ℃保存。用相应的引物以及荧光定量试剂盒对靶基因的mRNA水平进行测定[以ACTB (编码β-actin) 为内参]。实验中涉及的引物序列如下: 人KLF2 (forward: 5′-TGGAGGCCAAGCCAAAG-3′, reverse: 5′-CGAACTCTTGGTGTAGGTCTTG-3′); 人VCAM1 (forward: 5′-GATTGGTGACTCCGTCTCATT-3′, reverse: 5′-CCTTCCCATTCAGTGGACTATC-3′); 人ICAM1 (forward: 5′-GTAGCAGCCGCAGTCATAAT-3′, reverse: 5′-GGGCCTGTTGTAGTCTGTATTT-3′); 人ACTB (forward: 5′-GGACCTGACTGACTACCTCAT-3′, reverse: 5′- CGTAGCACAGCTTCTCCTTAAT-3′)。

细胞转染和荧光素酶活性检测 KLF2荧光素酶活性按照文献^{[15, 16]}所述方法进行检测。将处于对数生长期的COS-7细胞接种于96孔白底细胞培养板中, 利用脂质体将KLF2荧光素酶报告质粒(每孔0.2 μg) 转染进COS-7细胞中, 6 h后加入含有不同浓度TSC (0.001、0.01、0.1、1.0、2.5、5.0、10和20 μmol·L^-1) 的培养基继续培养24 h。利用荧光素酶检测试剂盒和酶标仪测定KLF2的荧光素酶活性。对于HDAC抑制活性的检测, 将不同亚型的HDAC过表达质粒与KLF2报告质粒共同转染进接种于96孔板的COS-7细胞中, 接下来的实验操作如上述所示。

分子对接实验 利用ChemDraw 14.0软件得到TSC的三维结构示意图, 使用Discovery Studio 4.5软件对TSC和HDAC4 (PDB编码: A69)、HDAC5 (PDB编码: 5UWI) 和HDAC7 (PDB编码: 3C10) 进行分子对接。通过LibDock的得分对受体-配体的亲和力进行评估。

统计学分析 所有实验数据均以平均值±标准误(mean ± SEM) 表示, 采用GraphPad Prim 8软件进行统计学分析, 组间统计学差异采用one-way ANOVA和student's t检验进行比较, P < 0.05时认为其具有统计学意义。

结果

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1 化合物TSC的分离纯化与结构鉴定

本研究利用实验室前期建立的KLF2表达上调剂筛选模型^{[15, 16]}筛选得到链霉菌CPCC 203909, 通过KLF2活性追踪、硅胶柱层析、闪式C18柱及半制备高效液相色谱, 从该菌株的大米发酵次级代谢产物中分离纯化得到了一个能上调KLF2表达的活性化合物。该化合物为白色无定形粉末, ESI-MS给出准分子离子峰m/z 465.2 [M+H]⁺, 分子式为C₂₃H₃₂N₂O₈。¹H NMR (600 MHz, CD₃OD-d₄) δ_H: 5.87 (1H, d, J=15.6 Hz, H-2), 7.27 (1H, d, J=15.6 Hz, H-3), 5.97 (1H, d, J=9.0 Hz, H-5), 4.54 (1H, dq, J=9.6, 6.0 Hz, H-6), 7.86 (2H, d, J=8.4 Hz, H-9, 13), 6.72 (2H, d, J=9.0 Hz, H-10, 12), 1.93 (3H, s, 4-Me), 1.27 (3H, d, J=6.5 Hz, 6-Me), 3.05 (3H, s, N-Me₂), 3.34 (1H, d, J=10.8, 6.6 Hz, H-2′), 3.40 (1H, t, J=9.0 Hz, H-3′), 3.28 (1H, t, J=9.6 Hz, H-4′), 3.34 (1H, m, H-5′), 3.67 (1H, dd, J=12.0, 2.4 Hz, H-6′), 3.91 (1H, dd, J=12.0, 6.0 Hz, H-6′); ¹³C NMR (600 MHz, CD₃OD-d₄) δ_C: 167.0 (C-1), 116.3 (C-2), 147.8 (C-3), 134.4 (C-4), 142.7 (C-5), 41.8 (C-6), 201.4 (C-7), 124.8 (C-8), 132.1 (C-9, 13), 112.1 (C-10, 12), 155.6 (C-11), 12.9 (4-Me), 18.4 (6-Me), 40.2 (M-Me₂), 107.8 (C-1′), 73.2 (C-2′), 77.6 (C-3′), 71.4 (C-4′), 28.5 (C-5′), 62.9 (C-6′)。以上数据与文献^[17]报道基本一致, 故鉴定化合物为曲古抑菌素C (TSC) (图 1A、B)。此外, 细胞毒性实验结果显示, TSC在40 μmol·L^-1内没有明显的细胞毒性(图 1C), 后续实验均在40 μmol·L^-1以内进行。

2 化合物TSC上调KLF2 mRNA的表达水平

利用KLF2表达上调剂筛选模型^{[15, 16]}, 本研究测定了TSC对KLF2的调节作用。研究结果显示, TSC在10和20 μmol·L^-1时上调KLF2的活性超过80倍, EC₅₀为1.38 μmol·L^-1 (图 2A)。RT-qPCR实验结果表明, TSC能剂量依赖性增加HUVECs中KLF2的mRNA水平, 并且给予HUVECs 10 μmol·L^-1 TSC处理24 h后, HUVECs中KLF2的mRNA水平能够上升1.5倍左右(图 2B); 此外, TNFα刺激可以降低HUVECs中KLF2的mRNA水平, TSC (5和10 μmol·L^-1) 处理后能够逆转TNFα诱导的KLF2 mRNA水平的下调(图 2C)。结果表明, TSC能上调HUVECs中KLF2的mRNA水平。

3 化合物TSC减少TNFα诱导的单核细胞黏附于内皮细胞

本研究利用TNFα刺激内皮细胞构建内皮细胞炎症模型^{[7, 18]}。研究结果发现, 与对照组相比, TNFα刺激能够显著增加单核细胞(THP-1) 黏附到HUVECs上的数量; 与TNFα刺激组相比, TSC (5和10 μmol·L^-1) 处理HUVECs 24 h后可以显著减少TNFα诱导的THP-1黏附数量的增加(图 3A、B)。

4 化合物TSC减少TNFα诱导的VCAM-1的表达

本研究利用TNFα刺激的内皮细胞^{[7, 18]}, 考察TSC对TNFα刺激后VCAM-1和ICAM-1蛋白以及mRNA水平的影响。如图 4A~C所示, TNFα刺激后, VCAM-1和ICAM-1的蛋白及mRNA水平均显著升高, 表明TNFα能够诱导内皮细胞炎症。给予不同浓度的TSC处理HUVECs 24 h后, 与TNFα刺激组相比, TSC能够浓度依赖性地降低VCAM-1的蛋白及mRNA水平, 但没有降低ICAM-1的蛋白及mRNA水平。因此, 本研究认为TSC对TNFα刺激所导致的内皮细胞炎症和单核细胞黏附数量增多的抑制作用主要依赖于增加KLF2的表达，以及减少黏附分子VCAM-1的表达。

5 化合物TSC通过抑制HDAC4、HDAC5和HDAC7上调KLF2

有研究发现, 抑制HDAC的活性能够上调KLF2的表达, 发挥减弱内皮细胞炎症的作用^{[19, 20]}。为了研究HDAC亚型与KLF2表达之间的关系, 本研究首先将HDAC 1~8亚型过表达质粒与KLF2报告质粒共同转染进COS-7细胞中, 通过检测荧光值反映HDAC是否会影响KLF2的表达。如图 5A所示, HDAC4、HDAC5或HDAC7能够抑制KLF2的荧光素酶活性, 本研究认为, HDAC4、HDAC5或HDAC7可以抑制KLF2的表达。接下来, 本研究继续探索了TSC对于HDAC4、HDAC5和HDAC7的作用。如图 5B所示, TSC逆转了由HDAC4、HDAC5或HDAC7引起的KLF2荧光素酶活性抑制, 这表明TSC对HDAC4、HDAC5和HDAC7亚型有抑制作用, 进而上调KLF2水平。

为了研究TSC与HDAC4、HDAC5和HDAC7蛋白相互作用的模式, 本研究使用Discovery Studio 4.5软件对TSC与HDAC4、HDAC5和HDAC7蛋白分别进行了分子对接实验。实验结果显示, TSC与HDAC4、HDAC5和HDAC7蛋白相互作用的Libdock得分分别为128.86、161.68和126.29, 表现出较强的亲和力, 范德华力是其主要的相互作用力(图 6)。综上所述, 化合物TSC通过抑制HDAC4、HDAC5和HDAC7亚型, 上调内皮细胞中KLF2的水平, 抑制VCAM-1的表达, 减少单核细胞黏附到内皮细胞上的数量, 进而抑制内皮细胞炎症。

讨论

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动脉粥样硬化是一种由脂质代谢紊乱引起的慢性炎症性疾病, 是冠心病、稳定性心绞痛和缺血性心脏病等多种CVD的基础^{[21, 22]}。炎症会促使内皮细胞分泌VCAM-1和ICAM-1等黏附分子, 吸引血液循环中的单核细胞黏附到内皮细胞, 促进动脉粥样硬化的发生发展^{[18, 23]}。KLF2作为动脉粥样硬化的一种保护因子, 可以抑制黏附分子VCAM-1和ICAM-1的表达, 减弱内皮细胞炎症及单核细胞黏附^[24]。因此, 发现KLF2小分子上调剂可能会对炎症引起的内皮功能障碍甚至动脉粥样硬化起到预防和治疗作用。

本研究利用KLF2表达上调剂筛选模型, 筛选得到一株链霉菌CPCC 203909, 该菌株大米发酵的次级代谢产物具有上调KLF2的活性。通过活性追踪, 分离纯化得到了一个活性化合物, 经过与文献对比确定其结构为TSC。本研究发现, TSC能够上调HUVECs中KLF2的mRNA水平, 并且逆转TNFα刺激诱导的KLF2 mRNA水平下降, 显著抑制TNFα刺激所导致的黏附分子VCAM-1的表达和单核细胞黏附。有研究表明, HDAC4、HDAC5和HDAC7能够抑制KLF2的表达, 曲古抑菌素A (trichostatin A, TSA) 作为HDAC泛抑制剂可以抑制VCAM-1的表达^{[19, 25-27]}。本研究发现, TSC也表现出抑制HDAC4、HDAC5和HDAC7的活性, 进而上调KLF2的表达, 抑制VCAM-1的表达。目前, 对TSC的研究主要集中在肿瘤领域, TSC具有一定的组蛋白去乙酰化酶抑制活性, 可以诱导小鼠白血病细胞分化^{[28, 29]}, 抑制KM12人结肠癌细胞的生长^[30]。

TSC是TSA的结构类似物, 它在TSA的羟肟基团上连接了一个阿尔法构型的葡萄糖。实验室前期从链霉菌CPCC 203909中分离并鉴定了化合物TSA, 研究发现TSA显著上调B类Ⅰ型清道夫受体(scavenger receptor class B type Ⅰ, SR-BI) 及其人类同源物CLA-1以及ATP结合盒转运体A1 (ABCA1) 的mRNA和蛋白水平, 剂量依赖性地增加小鼠巨噬细胞(RAW 264.7) 对高密度脂蛋白(high-density lipoprotein, HDL) 的摄取及对胆固醇的排出^{[31, 32]}。曲古抑菌素D (trichostatin D, TSD) 是TSC的结构类似物, 两者的结构在于糖的构型不同。本课题组前期从链霉菌CPCC 203909分离得到TSD, 发现其可以上调SR-BI和CLA-1表达, 增加RAW264.7对DiI-HDL的结合^[33]; 实验室前期还发现TSD可以上调KLF2的表达, 通过NOD样受体蛋白3信号通路在内皮细胞中发挥抗炎作用^[34]。此外, 本课题组前期已经发表他汀类药物辛伐他汀和阿托伐他汀对KLF2的上调作用, 其在KLF2模型上的EC₅₀分别为1.74和5.14 μmol·L^-1, 最大上调倍数分别为7.8和12.4倍^{[15, 34]}。由此可见, TSC对KLF2的调节作用要优于辛伐他汀和阿托伐他汀。基于以上结果推测, TSC等HDAC抑制剂具有预防和治疗动脉粥样硬化的潜力。

综上所述, 本研究从链霉菌CPCC 203909大米发酵次级代谢产物中成功分离得到化合物TSC, 并证明了TSC通过抑制HDAC4、HDAC5和HDAC7上调内皮细胞中KLF2的表达, 从而抑制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。

作者贡献: 司书毅、许艳妮、余利岩、陈明华和雷丽娟构思并设计实验和论文撰写。雷丽娟、许艳妮和陈明华进行论文实验和数据分析; 雷丽娟、陈渝川、张语嫣、巫晔翔、张煜皓和张晶参与化合物的分离纯化工作; 雷丽娟、李迎红和赵丽萍参与分子对接实验; 雷丽娟、姜新海、王伟志、王晨吟、李顺旺、韩江雪、李依宁和盛任参与分子生物学实验及数据分析工作。

利益冲突: 所有作者均声明不存在利益冲突。

基金

收起

中国医学科学院医学与健康科技创新工程项目(2022-JKCS-10)
中国医学科学院医学与健康科技创新工程项目(2019-RC-HL-009)
中国医学科学院医学与健康科技创新工程项目(2021-1-I2M-030)
京津冀基础研究合作专项(19JCZDJC63900)
国家自然科学基金面上资助项目(81973328)

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2023年第58卷第8期

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doi: 10.16438/j.0513-4870.2022-1406

接收时间：2022-12-22
首发时间：2025-11-21
出版时间：2023-08-12

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收稿日期：2022-12-22
修回日期：2023-01-17

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)

中国医学科学院医学与健康科技创新工程项目(2019-RC-HL-009)

中国医学科学院医学与健康科技创新工程项目(2021-1-I2M-030)

京津冀基础研究合作专项(19JCZDJC63900)

国家自然科学基金面上资助项目(81973328)

作者信息

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

通讯作者:

*余利岩, Tel: 86-10-63187118, E-mail: yly@cpcc.ac.cn;

司书毅, Tel: 86-10-63180604, E-mail: sisyimb@hotmail.com;

许艳妮, Tel: 86-10-63180623, E-mail: xuyanniwendeng@hotmail.com

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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