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.
Highlights
Vascular adhesion protein-1 (VAP-1) was discovered already more than 25 years ago, when vascular molecules involved in leukocyte trafficking into inflamed synovium were searched for [108]
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
We have reported the reduction of the clinical disease score, synovial leukocyte infiltration, and cartilage damage after VAP-1 inhibitor treatment and VAP-1 knockout mice in adjuvant-induced arthritis and anti-collagen antibodyinduced arthritis [86]
Summary
Vascular adhesion protein-1 (VAP-1) was discovered already more than 25 years ago, when vascular molecules involved in leukocyte trafficking into inflamed synovium were searched for [108]. When leukocyte binding to cultured monolayers of VAP-1 expressing endothelial cells isolated from different sources (rabbit heart, human liver) is studied under physiologically relevant laminar shear stress, several anti-VAP-1 antibodies interfere with the multistep adhesion cascade (25, 65a, 117). Acute LPS-induced lung injury partially relies on a VAP-1-dependent component inasmuch SSAO inhibitors reduce leukocyte accumulation in bronchoalveolar lavage fluid and TNF-a production [34, 103, 120] This is in line with the aggravated LPS-mediated lung injury in transgenic mice overexpressing human VAP-1 in the endothelium [145].
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