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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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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.

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Acknowledgements

The authors wish to thank Ikuyo Hirose, Erdal Tan Ishizuka for their skillful technical assistance. The authors also wish to thank Dr. Yukihoko Mashima for his scientific advice. This work was supported by a Grant-in-Aid for Scientific Research (C) (17K11442, 15K10855, 17K11444) from the Japan Society for the Promotion of Science.

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Authors and Affiliations

  1. Laboratory of Ocular Cell Biology and Visual Science, Hokkaido University, N-15, W-7, Kita-ku, Sapporo, 060-8638, Japan

    Shiho Yoshida, Miyuki Murata, Kousuke Noda, Takashi Matsuda, Atsuhiro Kanda & Susumu Ishida

  2. Department of Ophthalmology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, N-15, W-7, Kita-ku, Sapporo, 060-8638, Japan

    Shiho Yoshida, Miyuki Murata, Kousuke Noda, Takashi Matsuda, Michiyuki Saito, Wataru Saito, Atsuhiro Kanda & Susumu Ishida

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  1. Shiho Yoshida
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Correspondence to Kousuke Noda.

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Conflicts of interest

S. Yoshida, None; M. Murata, None; K. Noda, None; T. Matsuda, None; M. Saito, None; W. Saito, None; A. Kanda, None; S. Ishida, None.

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Yoshida, S., Murata, M., Noda, K. et al. Proteolytic cleavage of vascular adhesion protein-1 induced by vascular endothelial growth factor in retinal capillary endothelial cells. Jpn J Ophthalmol 62, 256–264 (2018). https://doi.org/10.1007/s10384-017-0555-4

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  • DOI: https://doi.org/10.1007/s10384-017-0555-4

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