Baicalein reduces angiogenesis in the inflammatory microenvironment via inhibiting the expression of AP-1.
Baicalein reduces angiogenesis in the inflammatory microenvironment via inhibiting the expression of AP-1.
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DOI：
10.18632/oncotarget.13669
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发表时间：
2017-01-03
期刊：
影响因子：
--
通讯作者：
Lu N
中科院分区：
文献类型：
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作者：
Huang Y;Miao Z;Hu Y;Yuan Y;Zhou Y;Wei L;Zhao K;Guo Q;Lu N
越来越多的临床和实验研究表明，难治性慢性炎症可导致恶性肿瘤的发生，抗血管生成治疗可能是阻止其进展的有效方法。黄芩素（Baicalein）是黄芩中的主要活性黄酮类化合物之一，具有抑制血管生成、抗炎和抗肿瘤作用。但黄芩素对炎症微环境中内皮细胞的作用机制尚不清楚。本文通过体外培养人脐静脉内皮细胞（HUVEC）与THP-1条件培养基，研究了黄芩素的抗血管生成作用。黄芩素可抑制HUVECs管腔形成和主动脉微血管生长，减少鸡胚绒毛尿囊膜新生血管数量。这种抗血管生成作用主要是由于抑制HUVECs的运动、迁移和侵袭。此外，黄芩素可直接与AP-1结合，降低HUVECs中c-Jun和c-Fos的表达，并促进其蛋白酶体降解。黄芩素还能抑制c-Jun和c-Fos的核翻译、异源二聚体形成和DNA结合亲和力。体内基质胶栓塞实验进一步证实了黄芩素的抗血管生成作用。综上所述，我们的研究表明黄芩素可以通过抑制AP-1的转录活性在炎症微环境中发挥其抗血管生成作用，这表明黄芩素可能是治疗难治性慢性炎症的替代药物。
Increasing clinical and experimental studies have demonstrated that refractory chronic inflammation will result in malignant tumor and anti-angiogenic therapy may be an effective way to thwart the progression. Baicalein, one of the major active flavanoids found in Scutellaria baicalensis Georgi, has been exhibited potent anti-inflammation and anti-tumor effects by reducing angiogenesis. However, the exact mechanism of baicalein on endothelial cells in inflammatory microenvironment was not clear yet. Here, we investigated the anti-angiogenic effect of baicalein by incubating human umbilical vein endothelial cells (HUVECs) with THP-1 conditioned medium in vitro. The tube formation of HUVECs and microvessel outgrowth of rat aorta were attenuated, as well as the number of newly formed blood vessels in chicken chorioallantoic membrane (CAM) was reduced by baicalein. This anti-angiogenic effect was mainly on account of the inhibited motility, migration and invasion of HUVECs. In addition, mechanistic studies showed that baicalein could bind to AP-1 directly and the expression of c-Jun and c-Fos in HUVECs was reduced, accompanied by their increased proteasomal degradation. Besides, baicalein suppressed the nuclear translation, heterodimer formation and DNA binding affinity of c-Jun and c-Fos. What's more, the anti-angiogenic effect of baicalein was further confirmed by matrigel plug assay in vivo. Taken together, our study demonstrated that baicalein could exert its anti-angiogenic effect in the inflammation microenvironment via inhibiting the transcriptional activity of AP-1, which suggested that baicalein might be an alternative treatment against refractory chronic inflammation.