Shiho Yoshida1,2, Miyuki Murata1,2, Kousuke Noda3,4, Takashi Matsuda1,2, Michiyuki Saito2, Wataru Saito2, Atsuhiro Kanda1,2, Susumu Ishida1,2. 1. Laboratory of Ocular Cell Biology and Visual Science, Hokkaido University, N-15, W-7, Kita-ku, Sapporo, 060-8638, Japan. 2. Department of Ophthalmology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, N-15, W-7, Kita-ku, Sapporo, 060-8638, Japan. 3. Laboratory of Ocular Cell Biology and Visual Science, Hokkaido University, N-15, W-7, Kita-ku, Sapporo, 060-8638, Japan. nodako@med.hokudai.ac.jp. 4. Department of Ophthalmology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, N-15, W-7, Kita-ku, Sapporo, 060-8638, Japan. nodako@med.hokudai.ac.jp.
Abstract
PURPOSE: To investigate the mechanism of soluble vascular adhesion protein-1 (sVAP-1) accumulation induced by vascular endothelial growth factor (VEGF) in the vitreous of patients with diabetic retinopathy (DR). STUDY DESIGN: Experimental. METHODS: Protein levels of sVAP-1 and N epsilon-(hexanoyl)lysine (HEL), an oxidative stress marker, in the vitreous samples from patients with proliferative diabetic retinopathy (PDR) with or without intravitreal bevacizumab (IVB) injection were determined by ELISA. The effect of VEGF on both mRNA expression of Vap-1 and secretion of sVAP-1 in rat retinal capillary endothelial cells (TR-iBRB2) was analyzed by real-time PCR and western blotting, respectively. In addition, the impact of VEGF on production and activation ratios of matrix metalloproteinase (MMP)-2 and MMP-9 was examined by gelatin zymography. Hydrogen peroxide production and reactive oxygen species (ROS) levels were assessed in the supernatants of TR-iBRB2 cells treated with VEGF. RESULTS: IVB injection decreased vitreous levels of sVAP-1 and HEL in patients with PDR. VEGF stimulation released sVAP-1 protein from TR-iBRB2 cells as a consequence of membrane-anchored VAP-1 shedding by MMP-2 and MMP-9. In addition, VEGF increased hydrogen peroxide generation and ROS augmentation through spermine oxidation by sVAP-1 as semicarbazide-sensitive amine oxidase (SSAO) in the supernatant of cultured endothelial cells. CONCLUSIONS: The current data demonstrate that proangiogenic factor VEGF induces sVAP-1 release from retinal capillary endothelial cells and facilitates hydrogen peroxide generation via enzymatic property of sVAP-1, followed by the increase of oxidative stress, one of the crucial factors in the pathogenesis of DR.
PURPOSE: To investigate the mechanism of soluble vascular adhesion protein-1 (sVAP-1) accumulation induced by vascular endothelial growth factor (VEGF) in the vitreous of patients with diabetic retinopathy (DR). STUDY DESIGN: Experimental. METHODS: Protein levels of sVAP-1 and N epsilon-(hexanoyl)lysine (HEL), an oxidative stress marker, in the vitreous samples from patients with proliferative diabetic retinopathy (PDR) with or without intravitreal bevacizumab (IVB) injection were determined by ELISA. The effect of VEGF on both mRNA expression of Vap-1 and secretion of sVAP-1 in rat retinal capillary endothelial cells (TR-iBRB2) was analyzed by real-time PCR and western blotting, respectively. In addition, the impact of VEGF on production and activation ratios of matrix metalloproteinase (MMP)-2 and MMP-9 was examined by gelatin zymography. Hydrogen peroxide production and reactive oxygen species (ROS) levels were assessed in the supernatants of TR-iBRB2 cells treated with VEGF. RESULTS: IVB injection decreased vitreous levels of sVAP-1 and HEL in patients with PDR. VEGF stimulation released sVAP-1 protein from TR-iBRB2 cells as a consequence of membrane-anchored VAP-1 shedding by MMP-2 and MMP-9. In addition, VEGF increased hydrogen peroxide generation and ROS augmentation through spermine oxidation by sVAP-1 as semicarbazide-sensitive amine oxidase (SSAO) in the supernatant of cultured endothelial cells. CONCLUSIONS: The current data demonstrate that proangiogenic factor VEGF induces sVAP-1 release from retinal capillary endothelial cells and facilitates hydrogen peroxide generation via enzymatic property of sVAP-1, followed by the increase of oxidative stress, one of the crucial factors in the pathogenesis of DR.
Authors: Marko Salmi; Craig Stolen; Pekka Jousilahti; Gennady G Yegutkin; Päivi Tapanainen; Tuula Janatuinen; Mikael Knip; Sirpa Jalkanen; Veikko Salomaa Journal: Am J Pathol Date: 2002-12 Impact factor: 4.307
Authors: L P Aiello; R L Avery; P G Arrigg; B A Keyt; H D Jampel; S T Shah; L R Pasquale; H Thieme; M A Iwamoto; J E Park Journal: N Engl J Med Date: 1994-12-01 Impact factor: 91.245
Authors: Anna Filip; Soraya Taleb; Rümeyza Bascetin; Mohammad Jahangiri; Matthieu Bardin; Cindy Lerognon; Bruno Fève; Patrick Lacolley; Sirpa Jalkanen; Nathalie Mercier Journal: Front Cardiovasc Med Date: 2022-09-13
Authors: Quan Dong Nguyen; Yasir J Sepah; Brian Berger; David Brown; Diana V Do; Alberto Garcia-Hernandez; Sunil Patel; Firas M Rahhal; Yevgeniy Shildkrot; Ronny W Renfurm Journal: Int J Retina Vitreous Date: 2019-08-01