Specific activation of insulin-like growth factor-1 receptor by ginsenoside Rg5 promotes angiogenesis and vasorelaxation

Young Lai Cho, Sung Mo Hur, Ji Yoon Kim, Ji Hee Kim, Dong Keon Lee, Jongeon Choe, Moo Ho Won, Kwon Soo Ha, Dooil Jeoung, Sanghwa Han, Sungwoo Ryoo, Hansoo Lee, Jeong Ki Min, Young Guen Kwon, Dong Hyun Kim, Young Myeong Kim

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27 Citations (Scopus)

Abstract

Ginsenoside Rg5 is a compound newly synthesized during the steaming process of ginseng; however, its biological activity has not been elucidated with regard to endothelial function. We found that Rg5 stimulated in vitro angiogenesis of human endothelial cells, consistent with increased neovascularization and blood perfusion in a mouse hind limb ischemia model. Rg5 also evoked vasorelaxation in aortic rings isolated from wild type and high cholesterolfed ApoE-/- mice but not from endothelial nitric-oxide synthase (eNOS) knock-out mice. Angiogenic activity of Rg5 was highly associated with a specific increase in insulin-like growth factor-1 receptor (IGF-1R) phosphorylation and subsequent activation of multiple angiogenic signals, including ERK, FAK, Akt/eNOS/NO, and Gi-mediated phospholipase C/Ca2+/eNOS dimerization pathways. The vasodilative activity of Rg5 was mediated by the eNOS/NO/cGMP axis. IGF-1R knockdown suppressed Rg5-induced angiogenesis and vasorelaxation by inhibiting key angiogenic signaling and NO/cGMP pathways. In silico docking analysis showed that Rg5 bound with high affinity to IGF-1R at the same binding site of IGF. Rg5 blocked binding of IGF-1 to its receptor with an IC50 of ∼90 nmol/liter. However, Rg5 did not induce vascular inflammation and permeability. These data suggest that Rg5 plays a novel role asanIGF-1Ragonist,promotingtherapeutic angiogenesis and improving hypertension without adverse effects in the vasculature.

Original languageEnglish
Pages (from-to)467-477
Number of pages11
JournalJournal of Biological Chemistry
Volume290
Issue number1
DOIs
Publication statusPublished - 2015 Jan 2

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All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Cho, Y. L., Hur, S. M., Kim, J. Y., Kim, J. H., Lee, D. K., Choe, J., Won, M. H., Ha, K. S., Jeoung, D., Han, S., Ryoo, S., Lee, H., Min, J. K., Kwon, Y. G., Kim, D. H., & Kim, Y. M. (2015). Specific activation of insulin-like growth factor-1 receptor by ginsenoside Rg5 promotes angiogenesis and vasorelaxation. Journal of Biological Chemistry, 290(1), 467-477. https://doi.org/10.1074/jbc.M114.603142