Caffeic acid phenethyl ester reduces the secretion of vascular endothelial growth factor through the inhibition of the ROS, PI3K and HIF-1α signaling pathways in human retinal pigment epithelial cells under hypoxic conditions.
Choroidal neovascularization (CNV) can lead to progressive and severe visual loss. Vascular endothelial growth factor (VEGF) promotes the development of CNV. Caffeic acid phenethyl ester (CAPE), a biologically active component of the honeybee (Apis mellifera) propolis, has been demonstrated to have several interesting biological regulatory properties. The objective of this study was to determine whether treatment with CAPE results in the inhibition of the production of vascular endothelial growth factor (VEGF) in retinal pigment epithelial cells (RPE cells) under hypoxic conditions and to explore the possible underlying mechanisms. An in vitro experimental model of hypoxia was used to mimic an ischemic microenvironment for the RPE cells. Human RPE cells (ARPE-19) were exposed to hypoxia with or without CAPE pre-treatment. ARPE-19 cells were used to investigate the pathway involved in the regulation of VEGF production under hypoxic conditions, based on western blot analysis, enzyme-linked immunosorbent assay (ELISA) and electrophoretic mobility shift assay (EMSA). The amount of VEGF released from the hypoxia-exposed cells was significantly higher than that of the normoxic controls. Pre-treatment with CAPE suppressed the hypoxia-induced production of VEGF in the ARPE-19 cells, and this effect was inhibited through the attenuation of reactive oxygen species (ROS) production, and the inhibition of phosphoinositide 3-kinase (PI3K)/AKT and hypoxia-inducible factor-1α (HIF-1α) expression. These in vitro findings suggest that CAPE may prove to be a novel anti-angiogenic agent for the treatment of diseases associated with CNV.
Department of Neurosurgery, Busan Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea.
Sung Hwa
SH
Paeng
Department of Biomedical Engineering, and Center for Marine-Integrated Biomedical Technology (BK21 Plus), Pukyong National University, Busan, Republic of Korea.
Won-Kyo
WK
Jung
Department of Physiology, Kangwon National University School of Medicine, Chuncheon, Gangwon, Republic of Korea.
Won Sun
WS
Park
Marine Biodiversity Institute of Korea, Seocheon, Chungcheongnam-do, Republic of Korea.
Dae-Sung
DS
Lee
Laboratory of Immunobiology, Department of Marine Life Sciences, Jeju National University, Jeju, Republic of Korea.
Gi-Young
GY
Kim
Department of Biochemistry, College of Oriental Medicine, Dongeui University, Busan, Republic of Korea.
Yung Hyun
YH
Choi
Department of Microbiology, Busan Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea.
Su-Kil
SK
Seo
Department of Biochemistry, Busan Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea.
Won Hee
WH
Jang
Department of Internal Medicine, Busan Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea.
Jung Sik
JS
Choi
Department of Internal Medicine, Busan Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea.
Young-Min
YM
Lee
Department of Microbiology, Busan Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea.
Saegwang
S
Park
Department of Microbiology, Busan Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea.
Il-Whan
IW
Choi
D002109:Caffeic Acids / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D055213:Retinal Pigment Epithelium / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D002109:Caffeic Acids; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017382:Reactive Oxygen Species; D042461:Vascular Endothelial Growth Factor A; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C055494:caffeic acid phenethyl ester; D010626:Phenylethyl Alcohol