Vascular Adhesion Protein-1 as a Potential Therapeutic Target in Liver Disease PATRICIA F. LALOR, a CEREN TUNCER, a CHRIS WESTON, a AZUCENA MARTIN-SANTOS, a DAVID J. SMITH, b AND DAVID H. ADAMS a a Liver Research Laboratory, Institute of Biomedical Research, Division of Medicine, University of Birmingham, Birmingham, United Kingdom b Biotie Therapies Corp., Turku, Finland ABSTRACT: Vascular adhesion protein-1 (VAP-1) is a homodimeric, transmembrane sialoglycoprotein, and amine-oxidase enzyme constitu- tively 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 dis- ease, 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 activ- ity modestly decreases migration of normal lymphocytes across HSECs but has significant effects on the migration of peripheral blood lym- phocytes (PBLs) and liver-derived lymphocytes across HSECs. Engage- ment of VAP-1 results in PI3-kinase-dependent NF-B 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 activa- tion of other endothelial adhesive pathways, and activation of leukocyte by VAP-1 ligand occupancy all contribute to adhesion. The restricted ex- pression of VAP-1 and increased production of sVAP-1 in inflammatory liver disease confirm the validity of this molecule as a therapeutic target. KEYWORDS: VAP-1; Semicarbazide-sensitive amine oxidases; SSAO; liver; endothelium; leukocyte adhesion INTRODUCTION In common with the skin and mucosal surfaces, the liver is a major port for pathogen entry into the body and is also exposed to harmless food antigens Address for correspondence: Patricia F. Lalor, Liver Research Laboratory, Institute of Biomedical Research, Division of Medicine. University of Birmingham, Birmingham B15 2TT UK. Voice: +44- 121-415-8700; fax: +44-121-415-8701. p.f.lalor@bham.ac.uk Ann. N.Y. Acad. Sci. 1110: 485–496 (2007). C  2007 New York Academy of Sciences. doi: 10.1196/annals.1423.051 485