Zeng Zhi, Huang Wen-Dong, Gao Qi, Su Mei-Ling, Yang Yong-Fei, Liu Zhao-Chun, Zhu Bang-Hao
Department of Pharmacology, Cardiac and Cerebral Vascular Research Centre, Zhongshan School of Medicine, Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China.
Int J Mol Med. 2015 Sep;36(3):685-97. doi: 10.3892/ijmm.2015.2292. Epub 2015 Jul 22.
Arnebin-1, a naphthoquinone derivative, plays a crucial role in the wound healing properties of Zicao (a traditional wound healing herbal medicine). It has been noted that Arnebin-1, in conjunction with vascular endothelial growth factor (VEGF), exerts a synergistic pro-angiogenic effect on human umbilical vein endothelial cells (HUVECs) and accelerates the healing process of diabetic wounds. However, the mechanisms responsible for the pro-angiogenic effect of arnebin‑1 on HUVECs and its healing effect on diabetic wounds have not yet been fully elucidated. In this study, in an aim to elucidate these mechanisms of action of arnebin‑1, we investigated the effects of arnebin‑1 on the VEGF receptor 2 (VEGFR2) and the phosphoinositide 3-kinase (PI3K)‑dependent signaling pathways in HUVECs treated with VEGF by western blot analysis. The pro‑angiogenic effects of arnebin‑1 on HUVECs, including its effects on proliferation and migration, were evaluated by MTT assay, Transwell assay and tube formation assay in vitro. The expression levels of hypoxia-inducible factor (HIF)‑1α, endothelial nitric oxide synthase (eNOS) and VEGF were determined by western blot analysis in the HUVECs and wound tissues obtained from non‑diabetic and diabetic rats. CD31 expression in the rat wounds was evaluated by immunofluorescence staining. We found that the activation of the VEGFR2 signaling pathway induced by VEGF was enhanced by arnebin‑1. Arnebin‑1 promoted endothelial cell proliferation, migration and tube formation through the PI3K‑dependent pathway. Moreover, Arnebin‑1 significantly increased the eNOS, VEGF and HIF‑1α expression levels in the HUVECs and accelerated the healing of diabetic wounds through the PI3K‑dependent signaling pathway. CD31 expression was markedly enhanced in the wounds of diabetic rats treated with arnebin‑1 compared to the wounds of untreated diabetic rats. Therefore, the findings of the present study indicate that arnebin-1 promotes the wound healing process in diabetic rats by eliciting a pro-angiogenic response.
紫草酸B-1是一种萘醌衍生物，在紫草（一种传统的伤口愈合草药）的伤口愈合特性中起着关键作用。值得注意的是，紫草酸B-1与血管内皮生长因子（VEGF）协同作用，对人脐静脉内皮细胞（HUVECs）发挥协同促血管生成作用，并加速糖尿病伤口的愈合过程。然而，紫草酸B-1对HUVECs促血管生成作用及其对糖尿病伤口愈合作用的机制尚未完全阐明。在本研究中，为了阐明紫草酸B-1的这些作用机制，我们通过蛋白质印迹分析研究了紫草酸B-1对用VEGF处理的HUVECs中VEGF受体2（VEGFR2）和磷酸肌醇3-激酶（PI3K）依赖性信号通路的影响。通过MTT法、Transwell法和体外管形成试验评估了紫草酸B-1对HUVECs的促血管生成作用，包括其对增殖和迁移的影响。通过蛋白质印迹分析测定了从非糖尿病和糖尿病大鼠获得的HUVECs和伤口组织中缺氧诱导因子（HIF）-1α、内皮型一氧化氮合酶（eNOS）和VEGF的表达水平。通过免疫荧光染色评估大鼠伤口中CD31的表达。我们发现紫草酸B-1增强了VEGF诱导的VEGFR2信号通路的激活。紫草酸B-1通过PI3K依赖性途径促进内皮细胞增殖、迁移和管形成。此外，紫草酸B-1显著增加了HUVECs中eNOS、VEGF和HIF-1α的表达水平，并通过PI3K依赖性信号通路加速了糖尿病伤口的愈合。与未治疗的糖尿病大鼠伤口相比，用紫草酸B-1治疗的糖尿病大鼠伤口中CD31表达明显增强。因此，本研究结果表明，紫草酸B-1通过引发促血管生成反应促进糖尿病大鼠的伤口愈合过程。
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