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

Research output: Contribution to journalArticle

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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Somatomedin Receptors
Nitric Oxide Synthase Type III
Somatomedins
Vasodilation
Chemical activation
Panax
Phosphorylation
Dimerization
Endothelial cells
Capillary Permeability
Type C Phospholipases
Apolipoproteins E
Bioactivity
Insulin-Like Growth Factor I
Knockout Mice
Computer Simulation
Inhibitory Concentration 50
Blood
Ischemia
Extremities

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Cho, Young Lai ; Hur, Sung Mo ; Kim, Ji Yoon ; Kim, Ji Hee ; Lee, Dong Keon ; Choe, Jongeon ; Won, Moo Ho ; Ha, Kwon Soo ; Jeoung, Dooil ; Han, Sanghwa ; Ryoo, Sungwoo ; Lee, Hansoo ; Min, Jeong Ki ; Kwon, Young Guen ; Kim, Dong Hyun ; Kim, Young Myeong. / Specific activation of insulin-like growth factor-1 receptor by ginsenoside Rg5 promotes angiogenesis and vasorelaxation. In: Journal of Biological Chemistry. 2015 ; Vol. 290, No. 1. pp. 467-477.
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title = "Specific activation of insulin-like growth factor-1 receptor by ginsenoside Rg5 promotes angiogenesis and vasorelaxation",
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.",
author = "Cho, {Young Lai} and Hur, {Sung Mo} and Kim, {Ji Yoon} and Kim, {Ji Hee} and Lee, {Dong Keon} and Jongeon Choe and Won, {Moo Ho} and Ha, {Kwon Soo} and Dooil Jeoung and Sanghwa Han and Sungwoo Ryoo and Hansoo Lee and Min, {Jeong Ki} and Kwon, {Young Guen} and Kim, {Dong Hyun} and Kim, {Young Myeong}",
year = "2015",
month = "1",
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doi = "10.1074/jbc.M114.603142",
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Cho, YL, Hur, SM, Kim, JY, Kim, JH, Lee, DK, Choe, J, Won, MH, Ha, KS, Jeoung, D, Han, S, Ryoo, S, Lee, H, Min, JK, Kwon, YG, Kim, DH & Kim, YM 2015, 'Specific activation of insulin-like growth factor-1 receptor by ginsenoside Rg5 promotes angiogenesis and vasorelaxation', Journal of Biological Chemistry, vol. 290, no. 1, pp. 467-477. https://doi.org/10.1074/jbc.M114.603142

Specific activation of insulin-like growth factor-1 receptor by ginsenoside Rg5 promotes angiogenesis and vasorelaxation. / Cho, Young Lai; Hur, Sung Mo; Kim, Ji Yoon; Kim, Ji Hee; Lee, Dong Keon; Choe, Jongeon; Won, Moo Ho; Ha, Kwon Soo; Jeoung, Dooil; Han, Sanghwa; Ryoo, Sungwoo; Lee, Hansoo; Min, Jeong Ki; Kwon, Young Guen; Kim, Dong Hyun; Kim, Young Myeong.

In: Journal of Biological Chemistry, Vol. 290, No. 1, 02.01.2015, p. 467-477.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Specific activation of insulin-like growth factor-1 receptor by ginsenoside Rg5 promotes angiogenesis and vasorelaxation

AU - Cho, Young Lai

AU - Hur, Sung Mo

AU - Kim, Ji Yoon

AU - Kim, Ji Hee

AU - Lee, Dong Keon

AU - Choe, Jongeon

AU - Won, Moo Ho

AU - Ha, Kwon Soo

AU - Jeoung, Dooil

AU - Han, Sanghwa

AU - Ryoo, Sungwoo

AU - Lee, Hansoo

AU - Min, Jeong Ki

AU - Kwon, Young Guen

AU - Kim, Dong Hyun

AU - Kim, Young Myeong

PY - 2015/1/2

Y1 - 2015/1/2

N2 - 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.

AB - 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.

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