Human Vascular Adhesion Protein-1 (VAP-1) Plays a Critical Role in Lymphocyte–Endothelial Cell Adhesion Cascade Under Shear

Salmi, Marko; Tohka, Sami; Jalkanen, Sirpa

doi:10.1161/01.res.86.12.1245

Cited by 44 publications

(38 citation statements)

References 20 publications

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“…Previous results have indicated that full-length human SSAO transfected into HEC retains its adhesion function for freshly isolated PBMC (Salmi et al, 2000). The efficacy and specificity of enzymatic inhibitors at blocking such interactions in static conditions were evaluated in our study using LJP 1207 and other small molecule inhibitors.…”

Section: Resultsmentioning

confidence: 99%

Anti-Inflammatory Effects of Inhibiting the Amine Oxidase Activity of Semicarbazide-Sensitive Amine Oxidase

Salter–Cid¹,

Wang²,

O’Rourke³

et al. 2005

J Pharmacol Exp Ther

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Human semicarbazide-sensitive amine oxidase (SSAO) or vascular adhesion protein-1 (VAP-1) is a copper-containing amine oxidase (AOC3, EC 1.4.3.6) that has both enzymatic and adhesive function. SSAO catalyzes the oxidative deamination of primary amines, resulting in the formation of the corresponding aldehyde and release of hydrogen peroxide and ammonia. Membrane-bound SSAO is an inflammation-inducible endothelial cell adhesion molecule that mediates the interaction between leukocytes and activated endothelial cells in inflamed vessels. Both the direct adhesive and enzymatic functions seem to be involved in the adhesion cascade. LJP 1207 [NЈ-(2-phenyl-allyl)-hydrazine hydrochloride] is a potent (human SSAO IC 50 ϭ 17 nM), selective, and orally available SSAO inhibitor that blocks both the enzymatic and adhesion functions of SSAO/VAP-1. In a mouse model of ulcerative colitis, LJP 1207 significantly reduces mortality, loss of body weight, and colonic cytokine levels. Quantitative histopathological assessment of colitis activity in this model showed a highly significant suppression of inflammation, injury, and ulceration scores in the animals treated with the SSAO/VAP-1 inhibitor. LJP 1207 also reduced serum levels of tumor necrosis factor-␣ and interleukin 6 in lipopolysaccharide (LPS)-challenged mice and prolonged survival post-LPS-induced endotoxemia. Therapeutic and prophylactic administration of LJP 1207 in the rat carrageenan footpad model also markedly inhibited swelling and inflammation. Overall, the data suggest that small molecule SSAO/VAP-1 inhibitors may provide clinical benefit in the treatment of acute and chronic inflammatory diseases.SSAO is a copper-containing amine oxidase that converts primary amines into the corresponding aldehydes while releasing ammonia and hydrogen peroxide (Buffoni and Ignesti, 2000): RCH 2 NH 2 ϩ H 2 O ϩ O 2 3 RCHO ϩ NH 3 ϩ H 2 O 2 . The products of this reaction are notable for their pharmacologic activity. For example, formaldehyde and oxygen free radicals are produced when SSAO processes the physiological substrate methylamine.In mammals, two forms of SSAO have been identified: a tissue-bound form and a soluble plasma form (Lyles, 1996). Several lines of evidence suggest that soluble SSAO originates from the tissue-bound form through proteolytic cleavage (Stolen et al., 2004a). Membrane-bound SSAO is located in the plasma membrane and possesses a single transmembrane portion, a short intracytoplasmic tail, and a large extracellular domain that contains the active center (Li et al., 1998). It is a highly glycosylated dimer with a molecular mass of 180 kDa and contains two subunits and two cupric ions per mole. The active site, containing one Cu 2ϩ and one carbonyl cofactor identified as TPQ connected by a water molecule, is located inside each subunit and communicates with the solvent through a hydrophobic channel (Holt et al., 1998). The TPQ oxygen atoms are hydrogen-bonded to water molecules and/or to the side chain of a conserved amino acid.In contrast to the be...

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Section: Resultsmentioning

confidence: 99%

Anti-Inflammatory Effects of Inhibiting the Amine Oxidase Activity of Semicarbazide-Sensitive Amine Oxidase

Salter–Cid¹,

Wang²,

O’Rourke³

et al. 2005

J Pharmacol Exp Ther

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“…These results are in line with the data from frozen section assays, because the contributions of VAP-1 to the binding of these leukocyte subsets to synovial vasculature were also almost equal. In contrast, P-selectin, which accounts for the superior adhesion of mucosal macrophages to synovial venules, is lacking from these transfectants (24). Thus, VAP-1 can indeed support binding of all mononuclear leukocyte classes isolated from IBD gut.…”

Section: Recombinant Vap-1 Can Support Binding Of All Mucosal Leukocymentioning

confidence: 93%

“…In brief, Ax cells are a spontaneously immortalized cell line originating from endothelial cells of rat high endothelial vessels. The parental cells have lost their capacity to bind lymphocytes in vitro, but VAP-1 transfection reconstitutes the adhesion cascade (23,24). The VAP-1 or mock (ϭcontrol) transfectants were plated on microscopic slides within wax-pen circles.…”

Section: Transfectant Binding Assaymentioning

confidence: 99%

Human Leukocyte Subpopulations from Inflamed Gut Bind to Joint Vasculature Using Distinct Sets of Adhesion Molecules

Salmi

Jalkanen

2001

The Journal of Immunology

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119

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Reactive arthritis can be triggered by inflammatory bowel diseases. We hypothesized that migration of mucosal immune cells from inflamed gut to joints could contribute to the development of reactive arthritis. Here we isolated gut-derived leukocytes from patients with Crohn’s disease and ulcerative colitis. Using function-blocking mAbs and in vitro frozen section adhesion assays we studied whether these cells bind to synovial vessels and which molecules mediate the interaction. The results showed that mucosal leukocytes from inflammatory bowel diseased gut bind well to venules in synovial membrane. Small intestinal lymphocytes adhered to synovial vessels using multiple homing receptors and their corresponding endothelial ligands (CD18-ICAM-1, α4β7/α4β1-integrin-VCAM-1, L-selectin-peripheral lymph node addressins, and CD44). Of these, only ICAM-1 significantly supported binding of immunoblasts. In contrast, P-selectin glycoprotein ligand-1-P-selectin interaction accounted for practically all synovial adherence of mucosal macrophages. In addition, blocking of vascular adhesion protein-1 significantly inhibited binding of all these leukocyte subsets to joint vessels. We conclude that different leukocyte populations derived from inflamed gut bind avidly to synovial vessels using distinct repertoire of adhesion molecules, suggesting that their recirculation may contribute to the development of reactive arthritis in inflammatory bowel diseases.

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“…13,17 CHO cells expressing the extracellular regions of Siglec-11 and Siglec-G fused to the green fluorescent protein and membrane anchored through glycosylphosphatidylinositol were developed using a novel expression system (D.M.O. and P.R.C., manuscript in preparation).…”

Section: Cell Lines and Cell Culturementioning

confidence: 99%

“…and P.R.C., manuscript in preparation). The enzymatically inactive mutant CHO-VAP-1Y471F and the RGD mutant CHO-VAP-1D720A have been generated as described by Koskinen et al 7 and Salmi et al, 17 respectively.…”

Section: Cell Lines and Cell Culturementioning

confidence: 99%

Human Siglec-10 can bind to vascular adhesion protein-1 and serves as its substrate

Kivi

Elima

Aalto

et al. 2009

Blood

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Leukocytes migrate from the blood into areas of inflammation by interacting with various adhesion molecules on endothelial cells. Vascular adhesion protein-1 (VAP-1) is a glycoprotein expressed on inflamed endothelium where it plays a dual role: it is both an enzyme that oxidizes primary amines and an adhesin that is involved in leukocyte trafficking to sites of inflammation. Although VAP-1 was identified more than 15 years ago, the counterreceptor(s) for VAP-1 on leukocytes has remained unknown. Here we have identified Siglec-10 as a leukocyte ligand for VAP-1 using phage display screenings. The binding between Siglec-10 and VAP-1 was verified by different adhesion assays, and this interaction was also consistent with molecular modeling. Moreover, the interaction between Siglec-10 and VAP-1 led to increased hydrogen peroxide production, indicating that Siglec-10 serves as a substrate for VAP-1. Thus, the Siglec-10-VAP-1 interaction seems to mediate lymphocyte adhesion to endothelium and has the potential to modify the inflammatory microenvironment via the enzymatic end products. IntroductionMaintenance of an adequate immune defense is largely dependent on migration of circulating leukocytes from the vasculature into the surrounding tissue. Extravasation of leukocytes from the blood into the tissues is controlled by a multistep cascade, which involves numerous adhesion and signaling molecules. First, leukocytes tether and roll on the vascular endothelium, after which they adhere more strongly, arrest, and finally diapedese through the vessel wall. 1,2 One of the endothelial molecules involved in this cascade is a 180-kDa homodimeric glycoprotein, vascular adhesion protein-1 (VAP-1). 3 VAP-1 is mainly expressed on vascular endothelium, on smooth muscle cells, and on adipocytes. 4 It is rapidly translocated to the endothelial cell surface on inflammation, where it supports recruitment of leukocytes. 5,6 VAP-1 is involved in the rolling, firm adhesion, and transmigration phases of the extravasation cascade. Besides being an adhesin, VAP-1 is also an enzyme (semicarbazide sensitive amine oxidase, SSAO) and catalyzes oxidative deamination of a primary amine to an aldehyde with concomitant release of hydrogen peroxide and ammonium. 4 We and others have shown that VAP-1 supports leukocyte recruitment to sites of inflammation via both enzyme-activity-dependent and enzyme-activity-independent ways. Monoclonal anti-VAP-1 antibodies, which do not block the enzymatic activity of VAP-1, still block the binding of leukocytes to the endothelium in vitro and in vivo, and inhibitors of the enzymatic function of VAP-1 are able to effectively prevent the interaction between leukocytes and endothelium in vitro and in vivo. 7,8 Moreover, it has been recently shown that the end products generated by the catalytic activity of VAP-1, especially hydrogen peroxide, play a role in the regulation of other homing-associated molecules and thus enhance the inflammatory response. 9,10 Although VAP-1 has been known already for a long time and ...

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Human Vascular Adhesion Protein-1 (VAP-1) Plays a Critical Role in Lymphocyte–Endothelial Cell Adhesion Cascade Under Shear

Cited by 44 publications

References 20 publications

Anti-Inflammatory Effects of Inhibiting the Amine Oxidase Activity of Semicarbazide-Sensitive Amine Oxidase

Anti-Inflammatory Effects of Inhibiting the Amine Oxidase Activity of Semicarbazide-Sensitive Amine Oxidase

Human Leukocyte Subpopulations from Inflamed Gut Bind to Joint Vasculature Using Distinct Sets of Adhesion Molecules

Human Siglec-10 can bind to vascular adhesion protein-1 and serves as its substrate

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