Vascular adhesion protein-1 (VAP-1; AOC3) is the best characterized SRT1720 ic50 ectooxidase in terms of leukocyte traffic 3, 4. It belongs to the primary amine oxidases (also known as semicarbazide-sensitive amine oxidases). VAP-1 is expressed in vascular endothelial, smooth muscle and fat cells, and it catalyzes oxidative deamination of primary amines. Regarding endothelial cells, VAP-1 is expressed in most vessels intracellularly but, apparently, under normal (non-inflammatory) conditions it can be expressed on the luminal surface of only certain types of vessels such as high endothelial venules. In most other vessels such as flat-walled venules, VAP-1 is translocated

from cytoplasmic vesicles to the luminal surface only upon induction of inflammation. During

oxidative deamination of primary amines, the substrate (the primary amine) is converted into an aldehyde, and ammonium and hydrogen peroxide are released (Fig. 2). The aldehyde products are involved in non-enzymatic formation of advanced glycation end-products, which are aberrantly glycosylated proteins capable of triggering inflammation and vascular malfunction. The hydrogen peroxide, on the other hand, is a powerful redox-signaling molecule at low concentrations. In particular, it can alter cellular responsiveness by inactivating phosphatases Selleckchem Ferroptosis inhibitor within the cells. The role of VAP-1 in leukocyte trafficking has been demonstrated by the use of function-blocking antibodies (which block the binding between leukocytes and endothelium but do not interfere with VAP-1′s enzymatic activity), small molecule enzyme inhibitors and gene-deficient mice 3, 4. Lymphocyte, monocyte and granulocyte binding to vessels in various lymphatic and non-lymphatic tissues has been shown to be inhibited by anti-VAP-1 antibodies in in vitro frozen section assays. In vitro flow chamber assays have revealed that blocking of VAP-1 by Oxalosuccinic acid mAbs or enzyme inhibitors reduces leukocyte rolling and adhesion on and, in particular, transmigration through the treated endothelial monolayer

4, 5. The contribution of VAP-1 in leukocyte extravasation under physiological shear has been confirmed in multiple in vivo assays. In intravital videomicroscopy, inhibition of VAP-1 by mAbs or enzyme inhibitors, results in increased rolling velocity, reduced adhesion and reduced transmigration 4, 6. The same alterations are also seen in VAP-1-deficient mice 7 (Table 1). Finally, inflammatory reactions can be alleviated in multiple in vivo models, such as those for peritonitis, arthritis, hepatitis, autoimmune diabetes, diabetic retinopathy, age-related macular degeneration, ischemia-reperfusion injury, transplant rejection and colitis, by anti-VAP-1 mAbs or enzyme inhibitors 3, 4, 6, 8–12. In malignancies, VAP-1 inhibition results in a decreased influx of immune-suppressing myeloid-derived suppressor cells into the tumors 13.