Inhibition of vascular adhesion protein-1 suppresses endotoxin-induced uveitis

Kousuke Noda, Shinsuke Miyahara, Toru Nakazawa, Lama Almulki, Shintaro Nakao, Toshio Hisatomi, Haicheng She, Kennard L. Thomas, Rebecca C. Garland, Joan W. Miller, Evangelos S. Gragoudas, Yosuke Kawai, Yukihiko Mashima, Ali Hafezi-Moghadam

Research output: Contribution to journalArticlepeer-review

45 Citations (Scopus)

Abstract

Inflammatory leukocyte accumulation is a common feature of major ocular diseases, such as uveitis, diabetic retinopathy, and age-related macular degeneration. Vascular adhesion protein-1 (VAP-1), a cell surface and soluble molecule that possesses semi-carbazide-sensitive amine oxidase (SSAO) activity, is involved in leukocyte recruitment. However, the expression of VAP-1 in the eye and its contribution to ocular inflammation are unknown. Here, we investigated the role of VAP-1 in an established model of ocular inflammation, the endotoxin-induced uveitis (EIU), using a novel and specific inhibitor. Our inhibitor has a half-maximal inhibitory concentration (IC50) of 0.007 μM against human and 0.008 μM against rat SSAO, while its IC50 against the functionally related monoamine oxidase (MAO) -A and MAO-B is >10 μM. In the retina, VAP-1 was exclusively expressed in the vasculature, and its expression level was elevated during EIU. VAP-1 inhibition in EIU animals significantly suppressed leukocyte recruitment to the anterior chamber, vitreous, and retina, as well as retinal endothelial P-selectin expression. Our data suggest an important role for VAP-1 in the recruitment of leukocytes to the immune-privileged ocular tissues during acute inflammation. VAP-1 inhibition may become a novel strategy in the treatment of ocular inflammatory diseases.

Original languageEnglish
Pages (from-to)1094-1103
Number of pages10
JournalFASEB Journal
Volume22
Issue number4
DOIs
Publication statusPublished - 2008 Apr
Externally publishedYes

Keywords

  • Leukocyte recruitment
  • Ocular inflammation
  • Semicarbazide-sensitive amine oxidase

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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