期刊
DIABETES OBESITY & METABOLISM
卷 15, 期 3, 页码 224-233出版社
WILEY
DOI: 10.1111/dom.12008
关键词
high glucose; human retinal endothelial cells; KH902; migration; PlGF; sprouting; VEGF
资金
- National Natural Science Foundation of China [81170864, 30872819]
- Science and Technology Projects in Guangdong Province [2009B030801024]
- Program for New Century Excellent Talents in University [NCET-09-0809]
- Independent Innovation Foundation of Shandong University
Aims Vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) are upregulated in many ocular neovascular diseases such as diabetic retinopathy (DR). KH902 is a recombinant fusion protein with its binding ligand taken from the domains of VEGF receptor-1 (VEGFR-1) and VEGF receptor-2 (VEGFR-2) and can bind all VEGF-A isoforms and PlGF. The aim of this study was to investigate the underlying mechanisms of anti-angiogenic effects of KH902. Methods The toxic effect of KH902 on cultured human retinal endothelial cells (HRECs) was measured by Annexin V/PI staining and MTT assay. The concentrations of secreted VEGF and PlGF were measured by ELISA. The migration of HRECs was assessed by scratch wound and transwell assay. The sprouting of HRECs was determined by tube formation assay. The protein levels of Src, p-Src, PI3K, Akt1, p-Akt1, Erk1/2 and p-Erk1/2 were measured by Western blot. Results KH902 at the concentrations from 100?ng/ml to 100 mu g/ml had no cytotoxicity to cultured HRECs. KH902 bound not only VEGF165, but also PlGF that were secreted by HRECs under high glucose condition. A 500?ng/ml of KH902 significantly suppressed high glucose-induced migration and sprouting of HRECs through downregulating the expression of PI3K and inhibiting the activation of Src, Akt1 and Erk1/2. Conclusion Our study indicates that KH902 suppresses high glucose-induced migration and sprouting of HRECs through not only binding VEGF, but also PlGF to inhibit the activation of Src-Akt1-Erk1/2 pathway. KH902 is a drug that potentially inhibits angiogenic pathways involving in DR or other ocular neovascular diseases.
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