SMND-309 promotes angiogenesis in human umbilical vein endothelial cells through activating erythropoietin receptor/STAT3/VEGF pathways

被引:24
作者
Du, Guangying [1 ,2 ]
Zhu, Haibo [1 ,3 ]
Yu, Pengfei [1 ,3 ]
Wang, Hongbo [2 ,3 ]
He, Jie [3 ]
Ye, Liang [3 ]
Fu, Fenghua [2 ]
Zhang, Jinghai [1 ]
Tian, Jingwei [2 ,3 ]
机构
[1] Shenyang Pharmaceut Univ, Sch Life Sci & Biopharmaceut, Shenyang 110016, Liaoning, Peoples R China
[2] Yantai Univ, Sch Pharm, Yantai 264005, Shandong, Peoples R China
[3] Luye Pharma Grp Ltd, Nonclin Res Dept, State Key Lab Long Acting & Targeting Drug Delive, Yantai 264003, Shandong, Peoples R China
基金
中国国家自然科学基金;
关键词
SMND-309 ((2E)-2-{6-[(E)-2-carboxylvinyl]-2,3-dihydroxyphenyl}-3-(3,4-dihydroxyphenyl) propenoic acid); Salvianolic acid B derivative; Angiogenesis; Erythropoietin receptor; STAT3; SALVIANOLIC ACID-B; GROWTH-FACTOR; VEGF EXPRESSION; RATS; RECEPTOR; ISCHEMIA; DERIVATE; STAT3; IDENTIFICATION; BRAIN;
D O I
10.1016/j.ejphar.2012.12.013
中图分类号
R9 [药学];
学科分类号
100702 [药剂学];
摘要
The aim of the study is to investigate the direct angiogenic activities of SMND-309, a novel metabolite of salvianolic acid B, on human umbilical vein endothelial cells (HUVEC) in vitro and its potential molecular mechanisms. Effects of SMND-309 on proliferation and adhesion of HUVEC were measured using sulforhodamine B assay and cell adhesion assay kit, respectively. Effects of SMND-309 on migration and differentiation of HUVEC were examined through wound-healing assay and tube formation on matrigel method, respectively. Expressions of erythropoietin (EPO), EPO receptor, phosphorylated EPO receptor, signal transducer and activator of transcription 3 (STAT3), phosphorylated STAT3 and vascular endothelial growth factor (VEGF) were detected by Western blot. Knocking down EPO receptor gene and blocking the epidermal growth factor (EGF) receptor/Janus kinase 2 (JAK2) pathways were used to explore the potential mechanisms in SMND-309 induced angiogenesis. SMND-309 strongly induced the proliferation of HUVEC in a concentration-dependent manner within the concentrations of 1-30 mu g/ml and significantly promoted the adhesion of HUVEC to different extracellular matrix at 30 mu g/ml. SMND-309 at doses of 3, 10, 30 mu g/ml significantly enhanced the migration, capillary-like structure formation, and the levels of VEGF, phosphorylated EPO receptor and phosphorylated STAT3. Results from further experiments using HUVECEPO (receptor-) and AG-490 showed that SMND-309 activated EPO receptor first, and then stimulated JAK2/STAT3, which up-regulated the expression of VEGF, and resulted in the angiogenesis. These results clearly show that SMND-309 has powerful angiogenic activity on HUVEC, which is mostly correlated with the up-regulation of VEGF through EPO receptor/STAT3 signal pathways. (C) 2012 Elsevier B.V. All rights reserved.
引用
收藏
页码:173 / 180
页数:8
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