Vascular adhesion protein-1 regulates leukocyte transmigration rate in the retina during diabetes.
Vascular adhesion protein-1 (VAP-1) is an endothelial adhesion molecule that possesses semicarbazide-sensitive amine oxidase (SSAO) activity and is involved in leukocyte recruitment. Leukocyte adhesion to retinal vessels is a predominant feature of experimentally induced diabetic retinopathy (DR). However, the role of VAP-1 in this process is unknown. Diabetes was induced by i.p. injection of Streptozotocin in Long-Evans rats. The specific inhibitor of VAP-1, UV-002, was administered by daily i.p. injections. The expression of VAP-1 mRNA in the retinal extracts of normal and diabetic animals was measured by real-time quantitative polymerase chain reaction (PCR). Firm leukocyte adhesion was quantified in retinal flatmounts after intravascular staining with concanavalin A (ConA). Leukocyte transmigration rate was quantified by in vivo acridine orange leukocyte staining (AOLS). In diabetic rats, the rate of leukocyte transmigration into the retinal tissues of live animals was significantly increased, as determined by AOLS. When diabetic animals were treated with daily injections of the VAP-1 inhibitor (0.3 mg/kg), leukocyte transmigration rate was significantly reduced (P < 0.05). However, firm adhesion of leukocytes in diabetic animals treated with the inhibitor did not differ significantly from vehicle-treated diabetic controls. This work provides evidence for an important role of VAP-1 in the recruitment of leukocyte to the retina in experimental DR. Our results reveal the critical contribution of VAP-1 to leukocyte transmigration, with little impact on firm leukocyte adhesion in the retinas of diabetic animals. VAP-1 inhibition might be beneficial in the treatment of DR.
Noda
Kousuke
K
Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.
Nakao
Shintaro
S
Zandi
Souska
S
Engelstädter
Verena
V
Mashima
Yukihiko
Y
Hafezi-Moghadam
Ali
A
D006631:Amine Oxidase (Copper-Containing) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000276:immunology* / Q000378:metabolism; D003930:Diabetic Retinopathy / Q000276:immunology* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D036904:Leukocyte Rolling / Q000187:drug effects; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology*; D018921:Leukostasis / Q000276:immunology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D012171:Retinal Vessels / Q000187:drug effects / Q000276:immunology*; D013997:Time Factors
D001786:Blood Glucose; D015815:Cell Adhesion Molecules; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D006631:Amine Oxidase (Copper-Containing); C510433:vascular adhesion protein-1, rat