Specific activation of insulin-like growth factor-1 receptor by ginsenoside Rg5 promotes angiogenesis and vasorelaxation.
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/Ca(2+)/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.
From the Departments of Molecular and Cellular Biochemistry.
Young-Lai
YL
Cho
From the Departments of Molecular and Cellular Biochemistry.
Sung-Mo
SM
Hur
From the Departments of Molecular and Cellular Biochemistry.
Ji-Yoon
JY
Kim
From the Departments of Molecular and Cellular Biochemistry.
Ji-Hee
JH
Kim
From the Departments of Molecular and Cellular Biochemistry.
Dong-Keon
DK
Lee
Immunology, and.
Jongeon
J
Choe
Neurobiology, School of Medicine, and.
Moo-Ho
MH
Won
From the Departments of Molecular and Cellular Biochemistry.
Kwon-Soo
KS
Ha
the Departments of Biochemistry and.
Dooil
D
Jeoung
the Departments of Biochemistry and.
Sanghwa
S
Han
Life Sciences, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon-do 200-701, South Korea.
Sungwoo
S
Ryoo
Life Sciences, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon-do 200-701, South Korea.
Hansoo
H
Lee
the Department of Biochemistry, College of Science and Biotechnology, Yonsei University, Seoul 120-749, South Korea, and.
Jeong-Ki
JK
Min
the Department of Biochemistry, College of Science and Biotechnology, Yonsei University, Seoul 120-749, South Korea, and.
Young-Guen
YG
Kwon
the Department of Life and Nanopharmaceutical Sciences, College of Pharmacy, Kyung Hee University, Seoul 130-701, South Korea.
Dong-Hyun
DH
Kim
From the Departments of Molecular and Cellular Biochemistry, ymkim@kangwon.ac.kr.
Young-Myeong
YM
Kim
D043925:Angiogenesis Inducing Agents / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D036145:Ginsenosides / Q000494:pharmacology*; D006614:Hindlimb / Q000098:blood supply* / Q000187:drug effects / Q000473:pathology; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D007511:Ischemia / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018919:Neovascularization, Physiologic; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D046509:Tissue Culture Techniques; D010738:Type C Phospholipases / Q000235:genetics / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects*
D043925:Angiogenesis Inducing Agents; D001057:Apolipoproteins E; D036145:Ginsenosides; D034741:RNA, Small Interfering; C572381:ginsenoside Rg5; C519530:insulin-like growth factor-1, mouse; D007334:Insulin-Like Growth Factor I; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D017526:Receptor, IGF Type 1; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D010738:Type C Phospholipases
Angiogenesis; Endothelial Cell; Insulin-like Growth Factor (IGF); Insulin-like Growth Factor-1 Receptor; Nitric Oxide; Vascular Biology; Vascular Function