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Ginsenoside-Rg1 mediates a hypoxia-independent upregulation of hypoxia-inducible factor-1α to promote angiogenesis
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 angiot...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Netherlands
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3214261/ https://www.ncbi.nlm.nih.gov/pubmed/21964931 http://dx.doi.org/10.1007/s10456-011-9235-z |
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author | Leung, Kar-Wah Ng, Hoi-Man Tang, Maggie K. S. Wong, Chris C. K. Wong, Ricky N. S. Wong, Alice S. T. |
author_facet | Leung, Kar-Wah Ng, Hoi-Man Tang, Maggie K. S. Wong, Chris C. K. Wong, Ricky N. S. Wong, Alice S. T. |
author_sort | Leung, Kar-Wah |
collection | PubMed |
description | 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10456-011-9235-z) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-3214261 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | Springer Netherlands |
record_format | MEDLINE/PubMed |
spelling | pubmed-32142612011-12-09 Ginsenoside-Rg1 mediates a hypoxia-independent upregulation of hypoxia-inducible factor-1α to promote angiogenesis Leung, Kar-Wah Ng, Hoi-Man Tang, Maggie K. S. Wong, Chris C. K. Wong, Ricky N. S. Wong, Alice S. T. Angiogenesis Original Paper 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10456-011-9235-z) contains supplementary material, which is available to authorized users. Springer Netherlands 2011-10-02 2011 /pmc/articles/PMC3214261/ /pubmed/21964931 http://dx.doi.org/10.1007/s10456-011-9235-z Text en © The Author(s) 2011 https://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited. |
spellingShingle | Original Paper Leung, Kar-Wah Ng, Hoi-Man Tang, Maggie K. S. Wong, Chris C. K. Wong, Ricky N. S. Wong, Alice S. T. Ginsenoside-Rg1 mediates a hypoxia-independent upregulation of hypoxia-inducible factor-1α to promote angiogenesis |
title | Ginsenoside-Rg1 mediates a hypoxia-independent upregulation of hypoxia-inducible factor-1α to promote angiogenesis |
title_full | Ginsenoside-Rg1 mediates a hypoxia-independent upregulation of hypoxia-inducible factor-1α to promote angiogenesis |
title_fullStr | Ginsenoside-Rg1 mediates a hypoxia-independent upregulation of hypoxia-inducible factor-1α to promote angiogenesis |
title_full_unstemmed | Ginsenoside-Rg1 mediates a hypoxia-independent upregulation of hypoxia-inducible factor-1α to promote angiogenesis |
title_short | Ginsenoside-Rg1 mediates a hypoxia-independent upregulation of hypoxia-inducible factor-1α to promote angiogenesis |
title_sort | ginsenoside-rg1 mediates a hypoxia-independent upregulation of hypoxia-inducible factor-1α to promote angiogenesis |
topic | Original Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3214261/ https://www.ncbi.nlm.nih.gov/pubmed/21964931 http://dx.doi.org/10.1007/s10456-011-9235-z |
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