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Proteolytic cleavage of vascular adhesion protein-1 induced by vascular endothelial growth factor in retinal capillary endothelial cells

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Title: Proteolytic cleavage of vascular adhesion protein-1 induced by vascular endothelial growth factor in retinal capillary endothelial cells
Other Titles: VEGF induces the cleavage of VAP-1
Authors: Yoshida, Shiho Browse this author
Murata, Miyuki Browse this author
Noda, Kousuke Browse this author →KAKEN DB
Matsuda, Takashi Browse this author
Saito, Michiyuki Browse this author
Saito, Wataru Browse this author →KAKEN DB
Kanda, Atsuhiro Browse this author →KAKEN DB
Ishida, Susumu Browse this author →KAKEN DB
Keywords: vascular endothelial growth factor (VEGF)
vascular adhesion protein-1 (VAP-1)
semicarbazide-sensitive amine oxidase (SSAO)
matrix metalloproteinases (MMPs)
Issue Date: Mar-2018
Publisher: Springer
Journal Title: Japanese Journal of Ophthalmology
Volume: 62
Issue: 2
Start Page: 256
End Page: 264
Publisher DOI: 10.1007/s10384-017-0555-4
PMID: 29392528
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.
Rights: This is a post-peer-review, pre-copyedit version of an article published in Japanese Journal of Ophthalmology. The final authenticated version is available online at:
Type: article (author version)
Appears in Collections:医学院・医学研究院 (Graduate School of Medicine / Faculty of Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 村田 美幸

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