Specific Activation of Insulin-like Growth Factor-1 Receptor by Ginsenoside Rg5 Promotes Angiogenesis and Vasorelaxation

• Published in: The Journal of biological chemistry 2015-01, Vol.290 (1), p.467-477
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Angiogenesis; Angiogenesis Inducing Agents - pharmacology; Animals; Aorta - drug effects; Aorta - metabolism; Apolipoproteins E - deficiency; Apolipoproteins E - genetics; Cell Biology; Endothelial Cell; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Extracellular Signal-Regulated MAP Kinases - genetics; Extracellular Signal-Regulated MAP Kinases - metabolism; Focal Adhesion Kinase 1 - genetics; Focal Adhesion Kinase 1 - metabolism; Gene Expression Regulation; Ginsenosides - pharmacology; Hindlimb - blood supply; Hindlimb - drug effects; Hindlimb - pathology; Humans; Insulin-like Growth Factor (IGF); Insulin-Like Growth Factor I - genetics; Insulin-Like Growth Factor I - metabolism; Insulin-like Growth Factor-1 Receptor; Ischemia - drug therapy; Ischemia - genetics; Ischemia - metabolism; Ischemia - pathology; Mice; Neovascularization, Physiologic; Nitric Oxide; Nitric Oxide Synthase Type III - genetics; Nitric Oxide Synthase Type III - metabolism; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Receptor, IGF Type 1 - agonists; Receptor, IGF Type 1 - antagonists & inhibitors; Receptor, IGF Type 1 - genetics; Receptor, IGF Type 1 - metabolism; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; Signal Transduction; Tissue Culture Techniques; Type C Phospholipases - genetics; Type C Phospholipases - metabolism; Vascular Biology; Vascular Function; Vasodilation - drug effects
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M114.603142

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 cholesterol-fed 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 as an IGF-1R agonist, promoting therapeutic angiogenesis and improving hypertension without adverse effects in the vasculature.The mechanism by which ginsenoside Rg5 regulates vascular function remains unclear. Rg5 increases angiogenesis and vasorelxation by activating multiple signal transduction pathways downstream of insulin-like growth fastor-1 receptor (IGF-1R). Rg5 promotes endothelial cell function through activation of IGF-1R. These findings reveal a mechanism for the positive regulation of vascular function by Rg5-mediated IGF-1R activation.