Trichostatin D as a Novel KLF2 Activator Attenuates TNFα-Induced Endothelial Inflammation

作者：Lijuan Lei, Minghua Chen, Chenyin Wang, Xinhai Jiang, Yinghong Li, Weizhi Wang, Shunwang Li, Liping Zhao, Ren Sheng, Jiangxue Han, Yuyan Zhang, Yu‐Chuan Chen, Biying Yan, Yexiang Wu, Liyan Yu, Shuyi Si, Yanni Xu · 发表于：International Journal of Molecular Sciences · 年份：2022 · DOI：10.3390/ijms232113477 · 被引用次数：12 · 研究领域：Kruppel-like factors research、Cancer-related gene regulation、Myeloproliferative Neoplasms: Diagnosis and Treatment

Krüppel-like factor 2 (KLF2) is an atherosclerotic protective transcription factor that maintains endothelial cell homeostasis through its anti-inflammatory, anti-oxidant, and antithrombotic properties. The aim of this study was to discover KLF2 activators from microbial secondary metabolites and explore their potential molecular mechanisms. By using a high-throughput screening model based on a KLF2 promoter luciferase reporter assay, column chromatography, electrospray ionization mass spectrometry (ESI-MS), and nuclear magnetic resonance (NMR) spectra, trichostatin D (TSD) was isolated from the rice fermentation of Streptomyces sp. CPCC203909 and identified as a novel KLF2 activator. Real-time-quantitative polymerase chain reaction (RT-qPCR) results showed that TSD upregulated the mRNA level of KLF2 in endothelial cells. Functional assays showed that TSD attenuated monocyte adhesion to endothelial cells, decreased vascular cell adhesion protein 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) expression, and exhibited an anti-inflammatory effect in tumor necrosis factor alpha (TNFα)-induced endothelial cells. We further demonstrated through siRNA and western blot assays that the effects of TSD on monocyte adhesion and inflammation in endothelial cells were partly dependent on upregulating KLF2 expression and then inhibiting the NOD-like receptor protein 3 (NLRP3)/Caspase-1/interleukin-1beta (IL-1β) signaling pathway. Furthermore, histone deacetylase (HDAC) overexpre...