Pro-angiogenic activity of isoliquiritin on HUVECs in vitro and zebrafish in vivo through Raf/MEK signaling pathway

• Published in: Life sciences (1973) 2019-04, Vol.223, p.128-136
• Main Authors: Zhang, Xiao-Huan, Li, Chong-Yong, Lin, Qing-Hua, He, Zhi-Heng, Feng, Feng, He, Ming-Fang
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Angiogenesis; Antioxidants; Apoptosis; Blood vessels; Cardiovascular diseases; Cell adhesion & migration; Cell migration; Cell viability; Cerebrovascular diseases; Chemical compounds; Danio rerio; Embryos; Endothelial cells; Enzyme inhibitors; FLI-1 protein; Genotoxicity; Growth factors; Heart diseases; Herbal medicine; HUVECs; In vitro methods and tests; Inflammation; Inhibitors; Isoliquiritin; Kinases; Liquorice; MAP kinase; Medical treatment; Mental depression; Pharmacology; Pro-angiogenic activity; Protein-tyrosine kinase; Proteins; Raf protein; Signal transduction; Signaling; Tyrosine; Umbilical vein; Vascular diseases; Vascular endothelial growth factor; Vascular endothelial growth factor receptors; Zebrafish
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2019.03.026

Liquorice is a widely used herbal medicine for treating various diseases native to southern Europe and parts of Asia. Isoliquiritin (ISL), a licorice root-derived flavonoid, has been reported to exhibit antioxidant, anti-inflammatory, anti-genotoxic activity and anti-depression activities. This study was aimed to explore the pro-angiogenic activity of ISL and explicate the underlying mechanism. In vitro, ISL-treated human umbilical vein endothelial cells (HUVECs) were analyzed for cell viability, cell migration and tube formation. In vivo, pro-angiogenic effects were evaluated for the intersegmental vessels (ISVs) formation in transgenic zebrafish embryos [Tg(fli-1: EGFP)]. Furthermore, a blocking assay with eight pathways-specific kinase inhibitors were also used to determine the potential pro-angiogenic mechanism of ISL. ISL counteracted tyrosine kinase inhibitor II (VRI)-induced endothelial cell apoptosis and promoted cell migration and tube formation in HUVECs. ISL markedly rescued ISVs loss induced by VRI in zebrafish embryos, probably by activating vascular endothelial growth factor receptor-2 (VEGFR-2), phosphoinositide 3-kinase (PI3K), Raf and mitogen-activated protein kinase (MEK)-dependent signaling pathways. Our study first discovered and confirmed the pro-angiogenic activity of ISL both in HUVECs and zebrafish. Thus, ISL could be developed as a potential therapeutic agent by the role of pro-angiogenic activity for the treatment of cardiovascular diseases, cerebrovascular diseases and other vascular diseases.