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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 and Ali Hafezi-Moghadam^*,1

^* Department of Ophthalmology, Massachusetts Eye and Ear Infirmary and Harvard Medical School, Boston, Massachusetts, USA; and

R-Tech Ueno, Ltd., Tokyo, Japan

¹Correspondence: Angiogenesis Laboratory, 325 Cambridge St., 3rd Floor, Boston, MA 02114, USA. E-mail: ahm{at}meei.harvard.edu

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 semicarbazide-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.—Noda, K., Miyahara, S., Nakazawa, T., Almulki, L., Nakao, S., Hisatomi, T., She, H., Thomas, K. L., Garland, R. C., Miller, J. W., Gragoudas, E. S., Kawai, Y., Mashima, Y., Hafezi-Moghadam, A. Inhibition of vascular adhesion protein-1 suppresses endotoxin-induced uveitis.

Key Words: semicarbazide-sensitive amine oxidase • ocular inflammation • leukocyte recruitment

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