Exp Mol Med.  2017 Oct;49(10):e387. 10.1038/emm.2017.151.

20(S)-Protopanaxadiol enhances angiogenesis via HIF-1α-mediated VEGF secretion by activating p70S6 kinase and benefits wound healing in genetically diabetic mice

• Zhang EY
• Gao B
• Shi HL
• Huang LF
• Yang L
• Wu XJ
• Wang ZT

• KMID: 2395749
• DOI: http://doi.org/10.1038/emm.2017.151

Abstract

Impaired angiogenesis is one of the crucial factors that impede the wound healing process in diabetic foot ulcers (DFUs). In this study, we found that 20(S)-protopanaxadiol (PPD), an aglycone of ginsenosides in Panax notoginseng, stimulated angiogenesis and benefited wound healing in genetically diabetic mice. In HUVECs, PPD promoted cell proliferation, tube formation and VEGF secretion accompanied by increased nuclear translocalization of HIF-1α, which led to elevated VEGF mRNA expression. PPD activated both PI3K/Akt/mTOR and Raf/MEK/ERK signaling pathways in HUVECs, which were abrogated by LY294002 and PD98059. Furthermore, these two pathways had crosstalk through p70S6K, as LY294002, PD98059 and p70S6K siRNA abolished the angiogenic responses of PPD. In the excisional wound splinting model established in db/db diabetic mice, PPD (0.6, 6 and 60"‰mg"‰ml−1) accelerated wound closure, which was reflected by a significantly reduced wound area and epithelial gaps, as well as elevated VEGF expression and capillary formation. In addition, PPD activated PI3K/Akt/ERK signaling pathways, as well as enhanced p70S6K activity and HIF-1α synthesis in the wounds. Overall, our results revealed that PPD stimulated angiogenesis via HIF-1α-mediated VEGF expression by activating p70S6K through PI3K/Akt/mTOR and Raf/MEK/ERK signaling cascades, which suggests that the compound has potential use in wound healing therapy in patients suffering from DFUs.

MeSH Terms

Animals
Capillaries
Cell Proliferation
Diabetic Foot
Ginsenosides
Humans
Mice*
Panax notoginseng
Phosphotransferases*
Ribosomal Protein S6 Kinases, 70-kDa
RNA, Messenger
RNA, Small Interfering
Splints
Ulcer
Vascular Endothelial Growth Factor A*
Wound Healing*
Wounds and Injuries*
Ginsenosides
Phosphotransferases
RNA, Messenger
RNA, Small Interfering
Ribosomal Protein S6 Kinases, 70-kDa
Vascular Endothelial Growth Factor A