Ischemia-reperfusion injury is attenuated in VAP-1-deficient mice and by VAP-1 inhibitors.
Neutrophils mediate the damage caused by ischemia-reperfusion both at the site of primary injury and in remote organs. Vascular adhesion protein-1 (VAP-1) is an ectoenzyme expressed on endothelial cells and it has been shown to regulate leukocyte extravasation. Here we show for the first time using VAP-1-deficient mice that VAP-1 plays a significant role in the intestinal damage and acute lung injury after ischemia-reperfusion. Separate inhibition of VAP-1 by small molecule enzyme inhibitors and a function-blocking monoclonal antibody in WT mice revealed that the catalytic activity of VAP-1 is responsible for its pro-inflammatory action. The use of transgenic humanized VAP-1 mice also showed that the enzyme inhibitors alleviate both the ischemia-reperfusion injury in the gut and neutrophil accumulation in the lungs. These data thus indicate that VAP-1 regulates the inflammatory response in ischemia-reperfusion injury and suggest that blockade of VAP-1 may have therapeutic value.
Kiss
Jan
J
MediCity Research Laboratory, University of Turku, Turku, Finland.
Jalkanen
Sirpa
S
Fülöp
Ferenc
F
Savunen
Timo
T
Salmi
Marko
M
D055371:Acute Lung Injury / Q000209:etiology; D006631:Amine Oxidase (Copper-Containing) / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000502:physiology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D002384:Catalysis; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000502:physiology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015427:Reperfusion Injury / Q000517:prevention & control*
D000911:Antibodies, Monoclonal; D015815:Cell Adhesion Molecules; C076668:AOC3 protein, human; D006631:Amine Oxidase (Copper-Containing); C492678:semicarbazide-sensitive amine oxidase-vascular adhesion protein-1, mouse