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Resveratrol Inhibits Hypoxia-Induced Vascular Endothelial Growth Factor Expression and Pathological Neovascularization

 Christopher Seungkyu Lee  ;  Eun Young Choi  ;  Sung Chul Lee  ;  Hyoung Jun Koh  ;  Joon Haeng Lee  ;  Ji Hyung Chung 
 YONSEI MEDICAL JOURNAL, Vol.56(6) : 1678-1685, 2015 
Journal Title
Issue Date
Adult ; Animals ; Cell Survival/drug effects ; Choroidal Neovascularization/metabolism* ; Choroidal Neovascularization/pathology ; Humans ; Hypoxia/metabolism ; Hypoxia/physiopathology ; Hypoxia-Inducible Factor 1, alpha Subunit/drug effects* ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Mice ; Mice, Inbred C57BL ; Phosphatidylinositol 3-Kinases/antagonists & inhibitors ; Phosphatidylinositol 3-Kinases/physiology* ; Proteasome Endopeptidase Complex ; Proto-Oncogene Proteins c-akt/antagonists & inhibitors ; Proto-Oncogene Proteins c-akt/physiology* ; Retinal Pigment Epithelium/drug effects* ; Retinal Pigment Epithelium/metabolism ; Signal Transduction ; Stilbenes/administration & dosage ; Stilbenes/pharmacology* ; TOR Serine-Threonine Kinases/antagonists & inhibitors ; TOR Serine-Threonine Kinases/physiology* ; Ubiquitin ; Vascular Endothelial Growth Factor A/drug effects* ; Vascular Endothelial Growth Factor A/metabolism
Choroidal neovascularization ; hypoxia-inducible factor-1 ; resveratrol ; retinal pigment epithelium ; vascular endothelial growth factor
PURPOSE: To investigate the effects of resveratrol on the expression of hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor (VEGF) in human adult retinal pigment epithelial (ARPE-19) cells, and on experimental choroidal neovascularization (CNV) in mice. MATERIALS AND METHODS: ARPE-19 cells were treated with different concentrations of resveratrol and then incubated under hypoxic conditions with subsequent evaluation of cell viability, expression of HIF-1α, and expression of VEGF. The effects of resveratrol on the synthesis and degradation of hypoxia-induced HIF-1α were evaluated using inhibitors of the PI3K/Akt/mTOR and the ubiquitin proteasome pathways. In animal studies, CNV lesions were induced in C57BL/6 mice by laser photocoagulation. After 7 days of oral administration of resveratrol or vehicle, which began one day after CNV induction, image analysis was used to measure CNV areas on choroidal flat mounts stained with isolectin IB4. RESULTS: In ARPE-19 cells, resveratrol significantly inhibited HIF-1α and VEGF in a dose-dependent manner, by blocking the PI3K/Akt/mTOR signaling pathway and by promoting proteasomal HIF-1α degradation. In mice experiments, orally administered resveratrol significantly inhibited CNV growth in a dose-dependent manner. CONCLUSION: Resveratrol may have therapeutic value in the management of diseases involving pathological neovascularization.
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1. College of Medicine (의과대학) > Dept. of Ophthalmology (안과학교실) > 1. Journal Papers
Yonsei Authors
Koh, Hyoung Jun(고형준) ORCID logo https://orcid.org/0000-0002-5932-8516
Lee, Sung Chul(이성철) ORCID logo https://orcid.org/0000-0001-9438-2385
Lee, Christopher Seungkyu(이승규) ORCID logo https://orcid.org/0000-0001-5054-9470
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