Research Paper
Subject Category: Cardiovascular and pulmonary pharmacology
British Journal of Pharmacology (2007) 152, 207–215; doi:10.1038/sj.bjp.0707359; published online 2 July 2007
Ginsenoside Rb1 inhibits tube-like structure formation of endothelial cells by regulating pigment epithelium-derived factor through the oestrogen 
receptor
K W Leung1, L W T Cheung2, Y L Pon2, R N S Wong1, N K Mak1, T-Pd Fan3, S C L Au4, J Tombran-Tink5,6 and A S T Wong2
- 1Department of Biology, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
- 2Department of Zoology, University of Hong Kong, Hong Kong, China
- 3Department of Pharmacology, Angiogenesis and TCM Laboratory, University of Cambridge, Cambridge, UK
- 4Department of Physiology, The Chinese University of Hong Kong, Hong Kong, China
- 5Department of Neural and Behavioral Sciences, Penn State University, PA, USA
- 6Department of Ophthalmology, Yale University School of Medicine, New Haven, CT, USA
Correspondence: Dr AST Wong, Department of Zoology, University of Hong Kong, Hong Kong, China. E-mail: awong1@hku.hk
Received 4 January 2007; Revised 2 March 2007; Accepted 25 March 2007; Published online 2 July 2007.
Abstract
Background and purpose:
Angiogenesis is a crucial step in tumour growth and metastasis. Ginsenoside-Rb1 (Rb1), the major active constituent of ginseng, potently inhibits angiogenesis in vivo and in vitro. However, the underlying mechanism remains unknown. We hypothesized that the potent anti-angiogenic protein, pigment epithelium-derived factor (PEDF), is involved in regulating the anti-angiogenic effects of Rb1.
Experimental approaches:
Rb1-induced PEDF was determined by real-time PCR and western blot analysis. The anti-angiogenic effects of Rb1 were demonstrated using endothelial cell tube formation assay. Competitive ligand-binding and reporter gene assays were employed to indicate the interaction between Rb1 and the oestrogen receptor (ER).
Key results:
Rb1 significantly increased the transcription, protein expression and secretion of PEDF. Targeted inhibition of PEDF completely prevented Rb1-induced inhibition of endothelial tube formation, suggesting that the anti-angiogenic effect of Rb1 was PEDF specific. Interestingly, the activation of PEDF occurred via a genomic pathway of ER
. Competitive ligand-binding assays indicated that Rb1 is a specific agonist of ER, but not ER
. Rb1 effectively recruited transcriptional activators and activated an oestrogen-responsive reporter gene. Furthermore, Rb1-mediated PEDF activation and the subsequent inhibition of tube formation were blocked by the ER antagonist ICI 182,780 or transfection of ER siRNA, indicating ER dependence.
Conclusions and implications:
Here we show for the first time that the Rb1 suppressed the formation of endothelial tube-like structures through modulation of PEDF via ER. These findings demonstrate a novel mechanism of the action of this ginsenoside that may have value in anti-cancer and anti-angiogenesis therapy.
Keywords:
ginseng, angiogenesis, endothelial cells, PEDF, oestrogen receptor
Abbreviations:
Dex, dexamethasone; DPN, diarylpropionitrile; ER, oestrogen receptor; E2, 17-oestradiol; ERE, oestrogen responsive element; GR, glucocorticoid receptor; HUVEC, human umbilical vein endothelial cells; LBD, ligand-binding domain; PEDF, pigment epithelium-derived factor; PPT, propyl pyrazole triol
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