Kaempferol prevents angiogenesis of rat intestinal microvascular endothelial cells induced by LPS and TNF-? via inhibiting VEGF/Akt/p38 signaling pathways and maintaining gut-vascular barrier integrity
Kaempferol prevents angiogenesis of rat intestinal microvascular endothelial cells induced by LPS and TNF-? via inhibiting VEGF/Akt/p38 signaling pathways and maintaining gut-vascular barrier integrity
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Kaempferol 通过抑制 VEGF/Akt/p38 信号通路并维持肠血管屏障完整性来防止 LPS 和 TNF-α 诱导的大鼠肠道微血管内皮细胞的血管生成。
DOI：
10.1016/j.cbi.2022.110135
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发表时间：
2022-09-02
影响因子：
5.1
通讯作者：
Bian, Yifei
中科院分区：
文献类型：
--
作者：
Yu, Ruyang;Zhong, Jia;Bian, Yifei
山奈酚是天然植物提取物中的一种主要黄酮类化合物，在抗炎和抗癌药物中显示出巨大的潜力。然而，山奈酚对肠血管屏障（GVB）和阻止肠道微血管生成的活性位点的保护作用的潜在机制尚未报道。本研究旨在探讨山奈酚对脂多糖（LPS）和肿瘤坏死因子-α（TNF-α）诱导的屏障损伤的保护作用及其对肠道微血管生成的保护作用机制。我们的数据表明，LPS和TNF-α的组合激活大鼠肠微血管内皮细胞（RIMVEC）的炎症反应，导致血管内皮生长因子（VEGF）的过度表达。GVB的通透性和跨上皮电阻（TEER）以及RIMVEC的管状结构也受到显著影响。山奈酚（25、50和100 μ M）降低炎症因子分泌和GVB通透性，下调VEGF、p-Akt和缺氧诱导因子-1 α（HIF-1 α）的表达。同时减轻了紧密连接蛋白（TJs）的异常表达。此外，山奈酚可以通过调节管形成和VEGF/Akt通路的下游信号传导来防止Akt抑制剂（MK-2206 2 HCl）存在下的肠血管生成。此外，伤口愈合实验表明，山奈酚在p38抑制剂（SB 203580）存在下具有类似的作用，其直观地抑制RIMVEC的迁移并降低p38 MAPK信号传导。我们的研究结果表明，山奈酚在LPS和TNF-α诱导的炎症环境中表现出显着的抗炎作用。山奈酚通过阻碍RIMVEC的管形成和迁移来防止肠血管生成。它还抑制血管生成相关信号的表达，从而保护GVB。
Kaempferol is a major flavonoid found in natural plant extracts; it shows great potential in anti-inflammatory and anti-cancer medicine. However, the underlying mechanism of the protective action of kaempferol on the gutvascular barrier (GVB) and the active sites preventing intestinal micro-angiogenesis has not been reported. The purpose of our study is to investigate the protective effect of kaempferol on the barrier damage induced by lipopolysaccharide (LPS) and tumor necrosis factor-alpha (TNF-alpha), and its mechanism of protective action on intestinal micro-angiogenesis. Our data showed that the combination of LPS and TNF-alpha activates the inflammatory response of the rat intestinal microvascular endothelial cells (RIMVECs), leading to overexpression of vascular endothelial growth factors (VEGFs). Also, the permeability of GVB and transepithelial electrical resistance (TEER) constructed by Transwell and the tubular structure of RIMVEC were significantly affected. Kaempferol (25, 50, and 100 mu M) decreased the inflammatory factor secretion and GVB permeability, downregulated the expression of VEGFs, p-Akt, and hypoxia-inducible factor-1alpha (HIF-1 alpha). It also alleviated the abnormal expression of tight junction proteins (TJs). Moreover, kaempferol may prevents intestinal angiogenesis in the presence of Akt inhibitor (MK-2206 2HCl) by regulating tube formation and downstream signaling of the VEGF/Akt pathways. In addition, the wound healing test showed that kaempferol had a similar effect in the presence of p38 inhibitor (SB203580), which intuitively restrained the migration of RIMVECs and reduced the p38 MAPK signaling. Our results demonstrated that kaempferol exhibits significant anti-inflammatory effects in LPS and TNF-alpha induced inflammatory environments. Kaempferol prevents intestinal angiogenesis by impeding the tube formation and migration of RIMVECs. It also suppresses the expression of angiogenesis-related signals, thereby protecting the GVB.