Ginsenoside-Rg1 mediates a hypoxia-independent upregulation of hypoxia-inducible factor-1α to promote angiogenesis

• Published in: Angiogenesis (London) 2011-12, Vol.14 (4), p.515-522
• Main Authors: Leung, Kar-Wah, Ng, Hoi-Man, Tang, Maggie K. S., Wong, Chris C. K., Wong, Ricky N. S., Wong, Alice S. T.
• Format: Article
• Language: English
• Subjects: Biomedical and Life Sciences; Biomedicine; Blotting, Western; Cancer Research; Cardiology; Cell Biology; Cells, Cultured; Chromones - pharmacology; DNA Primers - genetics; Endothelial Cells - metabolism; Gene Expression Regulation - drug effects; Ginsenosides - isolation & purification; Ginsenosides - pharmacology; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Morpholines - pharmacology; Neovascularization, Physiologic - physiology; Oncology; Ophthalmology; Original Paper; Panax - chemistry; Phosphatidylinositol 3-Kinase - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Rhizome - chemistry; Ribosomal Protein S6 Kinases, 70-kDa - metabolism; RNA Interference; Umbilical Veins - cytology; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 0969-6970; 1573-7209
• DOI: 10.1007/s10456-011-9235-z

Hypoxia-inducible factor (HIF-1) is the key transcription regulator for multiple angiogenic factors and is an appealing target. Ginsenoside-Rg1, a nontoxic saponin isolated from the rhizome of Panax ginseng , exhibits potent proangiogenic activity and has the potential to be developed as a new angiotherapeutic agent. However, the mechanisms by which Rg1 promotes angiogenesis are not fully understood. Here, we show that Rg1 is an effective stimulator of HIF-1α under normal cellular oxygen conditions in human umbilical vein endothelial cells. HIF-1α steady-state mRNA was not affected by Rg1. Rather, HIF-1α protein synthesis was stimulated by Rg1. This effect was associated with constitutive activation of phosphatidylinositol 3-kinase (PI3K)/Akt and its effector p70 S6 kinase (p70 S6K ), but not extracellular-signal regulated kinase 1/2. We further revealed that HIF-1α induction triggered the expression of target genes, including vascular endothelial growth factor (VEGF). The use of small molecule inhibitors LY294002 or rapamycin to inhibit PI3K/Akt and p70 S6K activities, respectively, resulted in diminished HIF-1α activation and subsequent VEGF expression. RNA interference-mediated knockdown of HIF-1α suppressed Rg1-induced VEGF synthesis and angiogenic tube formation, confirming that the effect was HIF-1α specific. Similarly, the angiogenic phenotype could be reversed by inhibition of PI3K/Akt and p70 S6K . These results define a hypoxia-independent activation of HIF-1α, uncovering a novel mechanism for Rg1 that could play a major role in angiogenesis and vascular remodeling.