Histone deacetylase inhibitor reduces monocyte adhesion to endothelium through the suppression of vascular cell adhesion molecule-1 expression
Histone deacetylase inhibitor reduces monocyte adhesion to endothelium through the suppression of vascular cell adhesion molecule-1 expression
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DOI：
10.1161/01.atv.0000247247.89787.e7
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发表时间：
2006-12-01
影响因子：
8.7
通讯作者：
Minami, Takashi
中科院分区：
文献类型：
--
作者：
Inoue, Kenji;Kobayashi, Mika;Minami, Takashi
目的：肿瘤坏死因子(TNF)-α引起内皮细胞(EC)基因表达的大量变化，参与包括炎症在内的各种疾病的病理过程。方法与结果：人脐静脉内皮细胞暴露于肿瘤坏死因子-α4h前，用PI3激酶(LY294002)、组蛋白去乙酰基酶(HDAC)、从头蛋白合成(CHx)、蛋白酶体(MG-132)和GATA因子(K-11430)的抑制剂预先孵育，并用基因芯片进行分析。这些抑制剂均可减弱肿瘤坏死因子-α介导的血管细胞黏附分子-1(VCAM-1)的诱导，而单用MG-132可阻断细胞间黏附分子-1(ICAM-1)的刺激作用。此外，TSA通过抑制VCAM-1在体外和体内均阻断了肿瘤坏死因子-α介导的单核细胞黏附诱导。进一步分析表明，HDAC3在调节肿瘤坏死因子-α介导的血管内皮细胞黏附分子-1表达中起重要作用。结论：肿瘤坏死因子-α通过多条信号通路激活内皮细胞，这些通路可能是选择性靶向调节血管内皮细胞功能。此外，TSA在体内外通过抑制VCAM-1减少了单核细胞的黏附，提示TSA可能有助于减轻EC的炎症反应。
Objective - Tumor necrosis factor (TNF)-alpha initiates numerous changes in endothelial cell (EC) gene expression that contributes to the pathology of various diseases including inflammation. We hypothesized that TNF-alpha-mediated gene induction involves multiple signaling pathways, and that inhibition of one or more of these pathways may selectively target subsets of TNF-alpha-responsive genes and functions.Methods and Results - Human umbilical vein endothelial cells (ECs) were preincubated with inhibitors of PI3 kinase (LY294002), histone deacetylases (HDAC) (trichostatin A [TSA]), de novo protein synthesis (CHX), proteasome (MG-132), and GATA factors (K-11430) before exposure to TNF-alpha at 4 hours and analyzed by microarray. TNF-alpha-mediated induction of vascular cell adhesion molecule-1 (VCAM-1) was attenuated by all of these inhibitors, whereas in contrast, stimulation of intercellular adhesion molecule-1 (ICAM-1) was blocked by MG-132 alone. Moreover TSA blocked TNF-alpha-mediated induction of monocyte adhesion both in vitro and in vivo through the suppression of VCAM-1. Further analysis demonstrated that HDAC3 plays a significant role in the regulation of TNF-alpha-mediated VCAM-1 expression.Conclusions - TNF-alpha activates ECs via multiple signaling pathways, and these pathways may be selectively targeted to modulate EC function. Moreover, TSA treatment reduced monocyte adhesion via VCAM- 1 suppression in vitro and in vivo, suggesting that TSA might be useful for the attenuation of the inflammatory response in EC.