Vascular Adhesion Protein-1 as a Potential Therapeutic Target in Liver Disease

: Vascular adhesion protein‐1 (VAP‐1) is a homodimeric, transmembrane sialoglycoprotein, and amine‐oxidase enzyme constitutively expressed by hepatic endothelial cells, and as a soluble protein in serum (sVAP‐1). VAP‐1 mediates leukocyte adhesion and migration in an enzyme activity‐dependent manner. We wished to determine whether VAP‐1 blockade reduces leukocyte recruitment in inflammatory liver disease, and the mechanism by which this occurs. Our results show that VAP‐1 is upregulated in the liver and serum of patients with inflammatory liver disease. Expression is maintained on hepatic sinusoidal endothelial cells (HSECs) isolated from explanted livers. Blockade of VAP‐1 activity modestly decreases migration of normal lymphocytes across HSECs but has significant effects on the migration of peripheral blood lymphocytes (PBLs) and liver‐derived lymphocytes across HSECs. Engagement of VAP‐1 results in PI3‐kinase‐dependent NF‐κB activation and increased chemokine and adhesion molecule expression. Thus complex mechanisms regulate VAP‐1‐mediated recruitment of leukocytes. Direct binding to endothelial VAP‐1 protein, indirect enzyme‐dependent activation of other endothelial adhesive pathways, and activation of leukocyte by VAP‐1 ligand occupancy all contribute to adhesion. The restricted expression of VAP‐1 and increased production of sVAP‐1 in inflammatory liver disease confirm the validity of this molecule as a therapeutic target.