Abstract
BackgroundThe goal of this study was to investigate the anti-angiogenic activity of a novel peptide H-RN, derived from the hepatocyte growth factor kringle 1 domain (HGF K1), in a mouse model of corneal neovascularization. The anti-angiogenic effect of H-RN on vascular endothelial growth factor (VEGF)-stimulated cell proliferation, cell migration and endothelial cell tube formation was assessed in vitro using Human Umbilical Vein Endothelial Cells (HUVECs) and in vivo using a mouse cornea micropocket assay. Apoptosis and cell cycle arrest were assessed by flow cytometry. A scrambled peptide was used as a negative control.ResultsH-RN effectively inhibited VEGF-stimulated HUVEC proliferation, migration and tube formation on Matrigel, while a scrambled peptide exerted no effect. In the mouse model of corneal angiogenesis, VEGF-stimulated angiogenesis was significantly inhibited by H-RN compared to a scrambled peptide that had no such activity. VEGF protected HUVECs from apoptosis, while H-RN inhibited this protective effect of VEGF. VEGF significantly increased the proportion of cells in the S phase compared to control treated cells (p<0.05). Treatment with H-RN (1.5 mM) induced the accumulation of cells in G0/G1 phase, while the proportion of cells in the S phase and G2/M phase decreased significantly compared to control group (p<0.05).ConclusionsH-RN has anti-angiogenic activity in HUVECs and in a mouse model of VEGF-induced corneal neovascularization. The anti-angiogenic activity of H-RN was related to apoptosis and cell cycle arrest, indicating a potential strategy for anti-angiogenic treatment in the cornea.
Highlights
The goal of this study was to investigate the anti-angiogenic activity of a novel peptide H-RN, derived from the hepatocyte growth factor kringle 1 domain (HGF Hepatocyte growth factor kringle 1 domain (K1)), in a mouse model of corneal neovascularization
H-RN inhibits Human Umbilical Vein Endothelial Cells (HUVECs) proliferation To investigate the effect of H-RN on HUVEC proliferation, cells were exposed to vascular endothelial growth factor (VEGF) (100 ng/ml) alone and in combination with various concentrations of H-RN or scrambled peptide for 24 h
HUVECs migration towards VEGF is inhibited by H-RN we investigated the ability of H-RN to affect the migration of HUVECs using Transwell migration assays
Summary
The goal of this study was to investigate the anti-angiogenic activity of a novel peptide H-RN, derived from the hepatocyte growth factor kringle 1 domain (HGF K1), in a mouse model of corneal neovascularization. Many pathological processes affecting the cornea, including trauma, inflammation, infection, toxicity and nutritional insults, may lead to corneal neovascularization [1]. While this process may be beneficial in wound healing, clearance of infections and arresting progressive immune-mediated corneal melts, neovascularization may reduce corneal transparency by Clinical ophthalmologists have been challenged with the treatment of sight-threatening corneal neovascularization for over 100 years [8]. New therapeutic agents, including pegaptanib, ranibizumab and bevacizumab, are reported to be effective in inhibiting corneal neovascularization. The extremely high annual treatment cost of these agents has limited their widespread use and systemic adverse events have been reported [13,14]
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