title: SIRT1 mediated inhibition of VEGF/VEGFR2 signaling by Resveratrol and its relevance to choroidal neovascularization.
abstract: SIRT1, a NAD(+) -dependent histone deacetylase, has been shown to act as a key regulator of angiogenesis. The purpose of this study was to determine the effects of resveratrol (RSV, a SIRT1 activator) on the vascular endothelial growth factor receptor 2 (VEGFR2) signaling pathway and to establish its relevance to choroidal neovascularization (CNV), a blinding complication of age-related macular degeneration. Western blot and ELISA assay showed that RSV inhibited hypoxia-inducible factor (HIF)-1α accumulation and VEGF secretion induced by cobalt chloride (CoCl2) through SIRT1 in human retinal pigment epithelial (hRPE) cells. Furthermore, RSV down-regulated VEGFR2 phosphorylation and activation induced by VEGF in endothelial cells via SIRT1. Thus, the inhibitory effect of RSV on the HIF-1α/VEGF/VEGFR2 signaling axis is mediated, at least in part, through SIRT1. The results suggest that targeting SIRT1 could have therapeutic potential for the treatment of CNV.
authors.affiliation: Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China; Departments of Pathology, Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.
authors.forename: Huiming
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Departments of Pathology, Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.
authors.forename: Shikun
authors.initials: S
authors.lastname: He
authors.affiliation: Departments of Pathology, Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Spee
authors.affiliation: Doheny Eye Institute, Los Angeles, CA, USA.
authors.forename: Keijiro
authors.initials: K
authors.lastname: Ishikawa
authors.affiliation: Departments of Pathology, Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA. Electronic address: dhinton@usc.edu.
authors.forename: David R
authors.initials: DR
authors.lastname: Hinton
mesh_terms: D002460:Cell Line; D020256:Choroidal Neovascularization / Q000503:physiopathology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors; D010766:Phosphorylation; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects*; D056564:Sirtuin 1 / Q000502:physiology*; D013267:Stilbenes / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D013267:Stilbenes; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D000077185:Resveratrol
keywords: CNV; HIF-1α; RPE; Resveratrol; SIRT1; VEGFR2