Vascular Adhesion Protein-1: A Cell Surface Amine Oxidase in Translation

Abstract

Significance: Vascular adhesion protein-1 (VAP-1) is an ectoenzyme that oxidates primary amines in a reaction producing also hydrogen peroxide. VAP-1 on the blood vessel endothelium regulates leukocyte extravasation from the blood into tissues under physiological and pathological conditions. Recent Advances: Inhibition of VAP-1 by neutralizing antibodies and by several novel small-molecule enzyme inhibitors interferes with leukocyte trafficking and alleviates inflammation in many experimental models. Targeting of VAP-1 also shows beneficial effects in several other diseases, such as ischemia/reperfusion, fibrosis, and cancer. Moreover, soluble VAP-1 levels may serve as a new prognostic biomarker in selected diseases. Critical Issues: Understanding the contribution of the enzyme activity-independent and enzyme activity-dependent functions, which often appear to be mediated by the hydrogen peroxide production, in the VAP-1 biology will be crucial. Similarly, there is a pressing need to understand which of the VAP-1 functions are regulated through the modulation of leukocyte trafficking, and what is the role of VAP-1 synthesized in adipose and smooth muscle cells. Future Directions: The specificity and selectivity of new VAP-1 inhibitors, and their value in animal models under therapeutic settings need to be addressed. Results from several programs studying the therapeutic potential of VAP-1 inhibition, which now are in clinical trials, will reveal the relevance of this amine oxidase in humans.

Keywords: cancer; hydrogen peroxide; inflammation; leukocyte trafficking.

FIG. 1.

SSAOs/CAOs oxidate primary amines into aldehydes, ammonium and hydrogen peroxide in a two-step reaction. SSAOs/CAOs can be classified based on their enzymatic properties (cofactor, substrates) or molecular properties (gene sequences). AOC, amine oxidase copper containing; CAOs, copper-dependent amine oxidases; LOX, lysyl oxidase; LOXL, lysyl oxidase like; PEA, phenyl ethylamine; SSAOs, semicarbazide-sensitive amine oxidases.

FIG. 2.

Crystallographic structure of VAP-1. (A) Two identical monomers are colored blue and wheat. Copper (Cu) ion is orange and TPQ in each chain is presented as green spheres. (B) Docking of Siglec-9 peptide (green) into the active site of VAP-1. This binding mode is presented in Aalto et al. (1) and assumes that the peptide binds covalently to TPQ. Courtesy of Dr. Tiina Salminen. Siglec, sialic acid-binding immunoglobulin-type lectins; TPQ, topaquinone; VAP-1, vascular adhesion protein-1.

FIG. 3.

VAP-1 is expressed in vascular endothelium and smooth muscle in human liver and tonsil. Triple stainings using anti-VAP-1, anti-smooth muscle actin (SMA), and anti-CD31 (pan-endothelial antibodies) are shown. Note that liver sinusoids (arrowheads) stain brightly with anti-VAP-1 but are devoid of smooth muscle present in larger vessels. Similarly, smaller capillaries are VAP-1/CD31 positive but lack SMA in tonsil (arrows).

FIG. 4.

Functions of VAP-1 in health and disease. VAP-1 has multiple different physiological functions (blue boxes), and it is involved in their aberrations during different disease states (yellow boxes). Many of these processes are interdependent, and the role of VAP-1 in leukocyte extravasation is likely to contribute heavily to many of them.

FIG. 5.

A working model for VAP-1 function in the leukocyte extravasation cascade. A blood-borne leukocyte makes sequential contacts with the endothelial cell expressing VAP-1. When the two cell types (STEP 1) come in contact with each other (STEP 2), a leukocyte counter-receptor of VAP-1 interacts in an enzyme activity-independent manner with the endothelial VAP-1. Thereafter, the same (or another) leukocyte surface molecule is used as a substrate in the VAP-1-mediated oxidative deamination reaction (STEP 3). This results in the formation of a covalent but transient binding between the two cell types. After the catalytic reaction, the leukocyte surface molecule is modified into an aldehyde, a signaling molecule hydrogen peroxide is formed, and VAP-1 enzyme is converted back to the original state (STEP 4). Note that the order of the proposed STEPs 2 and 3 is hypothetical.

FIG. 6.

VAP-1 can be used as a target for imaging. Representative sagittal (left), transaxial (middle), and coronal (right) multiplane PET images of [¹⁸F]FDR-Siglec-9 (VAP-1 ligand) biodistribution in a rat. The images are summation from 10 to 60 min postinjection. Reproduced with permission from Chemical Communication [from Li et al. (73)].