dl-3n-Butylphthalide Promotes Angiogenesis Via the Extracellular Signal-regulated Kinase 1/2 and Phosphatidylinositol 3-Kinase/Akt-endothelial Nitric Oxide Synthase Signaling Pathways
dl-3n-Butylphthalide Promotes Angiogenesis Via the Extracellular Signal-regulated Kinase 1/2 and Phosphatidylinositol 3-Kinase/Akt-endothelial Nitric Oxide Synthase Signaling Pathways
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dl-3n-丁基苯酞通过细胞外信号调节激酶 1/2 和磷脂酰肌醇 3-激酶/Akt 内皮一氧化氮合酶信号通路促进血管生成
DOI：
10.1097/fjc.0b013e3182443e74
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发表时间：
2012-04-01
影响因子：
3
通讯作者：
Ou, Jing-song
中科院分区：
文献类型：
--
作者：
Lu, Xi-lin;Luo, Dan;Ou, Jing-song
翻译后摘要：我们以前已经证明，dl-3正丁基苯酞（NBP）具有潜在的血管生成活性。在这项研究中，我们研究了NBP的促血管生成作用和NBP介导的血管生成的分子机制。用不同剂量的NBP和几种信号通路抑制剂处理斑马鱼胚胎和人脐静脉内皮细胞。NBP诱导斑马鱼胚胎异位肠下血管生成，并以剂量依赖性方式诱导人脐静脉内皮细胞的侵袭、迁移和内皮细胞管形成。成纤维细胞生长因子受体1抑制剂SU 5402、细胞外信号调节激酶1/2（ERK 1/2）抑制剂U 0126、磷脂酰肌醇3-激酶抑制剂LY 294002、Akt抑制剂1 L 6-羟甲基-手性肌醇-2-（R）-2-O-甲基-3-O-十八烷基-sn-甘油碳酸酯、cavtratin，内皮型一氧化氮合酶（eNOS）抑制剂，并完全抑制U 0126和LY 294002的组合。NBP增强ERK 1/2和成纤维细胞生长因子受体2表达的磷酸化，这被U 0126抑制。NBP增加Akt和eNOS在丝氨酸1177处的磷酸化，这被LY 294002阻断。NBP刺激一氧化氮的产生，LY 294002可降低一氧化氮的产生。我们的数据表明，（1）NBP促进血管生成和（2）NBP的血管生成作用是通过ERK 1/2和磷脂酰肌醇3-激酶/Akt-eNOS信号通路介导的。我们的研究结果表明，NBP可能是一种新的治疗缺血性疾病的血管生成剂。
Abstract: We have previously demonstrated that dl-3n-butylphthalide (NBP) has a potential angiogenic activity. In this study, we investigated the angiogenic effect of NBP and the molecular mechanisms underlying NBP-mediated angiogenesis. Zebrafish embryos and human umbilical vein endothelial cells were treated with various doses of NBP and several signaling pathway inhibitors. NBP induced ectopic subintestinal vessel production in zebrafish embryos and induced invasion, migration, and endothelial cell tube formation of human umbilical vein endothelial cells in a dose-dependent manner. These NBP-induced angiogenic effects were partially suppressed by SU5402, a fibroblast growth factor receptor 1 inhibitor; U0126, an extracellular signal–regulated kinase 1/2 (ERK1/2) inhibitor; LY294002, a phosphatidylinositol 3-kinase inhibitor; 1L6-hydroxymethyl-chiro-inositol-2-(R)-2-O-methyl-3-O-octadecyl-sn-glycerocarbonate, an Akt inhibitor; cavtratin, an endothelial nitric oxide synthase (eNOS) inhibitor and completely inhibited by a combination of U0126 and LY294002. NBP enhanced phosphorylation of ERK1/2 and fibroblast growth factor receptor 2 expression, which were inhibited by U0126. NBP increased the phosphorylation of Akt and eNOS at serine 1177, which was blocked by LY294002. NBP-stimulated nitric oxide production, which was reduced by LY294002. Our data demonstrated that (1) NBP promoted angiogenesis and (2) the angiogenic effects of NBP were mediated by the ERK1/2 and phosphatidylinositol 3-kinase/Akt-eNOS signaling pathways. Our findings suggest that NBP could be a novel agent for therapeutic angiogenesis in ischemic diseases.