石斛联苄类化合物抑制血管新生的机制
Bibenzyl from Dendrobium inhibits angiogenesis and its underlying mechanism
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摘要:
联苄类是传统中药石斛中一类含量较多的活性化合物。本研究首先考察了从石斛属药用植物中分离得到的6种联苄类化合物抑制VEGF (vascular endothelial growth factor) 诱导的人脐静脉内皮细胞 (human umbilical vascular endothelial cell, HUVEC) 管腔形成的实验, 发现除tristin外其他联苄类化合物在10 μmol·L−1时均显示出了明显的抑制活性, 其中moscatilin的最低有效浓度为1 μmol·L−1。进一步研究表明, moscatilin能浓度依赖性地抑制VEGF诱导的HUVEC细胞管腔的形成。免疫印迹 (Western blotting) 结果表明, moscatilin能抑制VEGF诱导的VEGFR2 (vascular endothelial growth factor receptor 2, Flk-1/KDR) 及ERK1/2 (extracellular regulated protein kinases) 的磷酸化激活, 并能同时抑制由VEGF诱导的ERK1/2上游信号通路c-Raf和MEK1/2激酶的磷酸化。结果表明, moscatilin抑制血管新生活性的机制与阻断VEGFR2及c-Raf-MEK1/2-ERK1/2信号级联通路的激活有关。
Abstract:Bibenzyl is a type of active compounds abundant in Dendrobium. In the present study, we investigated the inhibitory effects of six bibenzyls isolated from Dendrobium species on vascular endothelial growth factor (VEGF)-induced tube formation in human umbilical vascular endothelial cells (HUVECs). All those bibenzyls inhibited VEGF-induced tube formation at 10 μmol·L−1 except tristin, and of which moscatilin was found to have the strongest activity at the same concentration. The lowest effective concentration of moscatilin was 1 μmol·L−1. Further results showed that moscatilin inhibited VEGF-induced capillary-like tube formation on HUVECs in a concentration-dependent manner. Western blotting results showed that moscatilin also inhibited VEGF-induced phosphorylation of VEGFR2 (Flk-1/KDR) and extracellular signal-regulated kinase 1/2 (ERK1/2). Further results showed that moscatilin inhibited VEGF-induced activation of c-Raf and MEK1/2, which are both upstream signals of ERK1/2. Taken together, results presented here demonstrated that moscatilin inhibited angiogenesis via blocking the activation of VEGFR2 (Flk-1/KDR) and c-Raf-MEK1/2-ERK1/2 signals.
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