Inhibition of vascular adhesion protein-1 suppresses endotoxin-induced uveitis.
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 (IC(50)) of 0.007 microM against human and 0.008 microM against rat SSAO, while its IC(50) against the functionally related monoamine oxidase (MAO) -A and MAO-B is >10 microM. 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
Kousuke
K
Department of Ophthalmology, Massachusetts Eye and Ear Infirmary and Harvard Medical School, Boston, Massachusetts, USA.
Miyahara
Shinsuke
S
Nakazawa
Toru
T
Almulki
Lama
L
Nakao
Shintaro
S
Hisatomi
Toshio
T
She
Haicheng
H
Thomas
Kennard L
KL
Garland
Rebecca C
RC
Miller
Joan W
JW
Gragoudas
Evangelos S
ES
Kawai
Yosuke
Y
Mashima
Yukihiko
Y
Hafezi-Moghadam
Ali
A
D006631:Amine Oxidase (Copper-Containing) / Q000037:antagonists & inhibitors*; D000818:Animals; D019556:COS Cells; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors*; D002522:Chlorocebus aethiops; D004731:Endotoxins / Q000633:toxicity*; D004791:Enzyme Inhibitors; D006801:Humans; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D008856:Microscopy, Fluorescence; D051381:Rats; D012160:Retina / Q000378:metabolism; D014605:Uveitis / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*
D015815:Cell Adhesion Molecules; D004731:Endotoxins; D004791:Enzyme Inhibitors; C076668:AOC3 protein, human; D006631:Amine Oxidase (Copper-Containing); C510433:vascular adhesion protein-1, rat