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

Salmi, Marko; Jalkanen, Sirpa

doi:10.1089/ars.2017.7418

Cited by 76 publications

(95 citation statements)

References 149 publications

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“…Bovine plasma amine oxidase is a copper-containing amine oxidase, an ortholog to the product of the human AOC3 gene (Amine Oxidase, Copper-Containing 3) [13,14]. This enzyme, also called semicarbazide-sensitive amine oxidase or vascular adhesion protein-1 (SSAO/VAP-1) is involved in mediating lymphocyte extravasation at sites of inflammation [15]. Pharmacological inhibitors of SSAO/VAP-1 are under development and are currently being considered for potential use as novel anti-inflammatory drugs [16,17].…”

Section: Introductionmentioning

confidence: 99%

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Methylxanthines Inhibit Primary Amine Oxidase and Monoamine Oxidase Activities of Human Adipose Tissue

et al. 2020

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Background: Methylxanthines including caffeine and theobromine are widely consumed compounds and were recently shown to interact with bovine copper-containing amine oxidase. To the best of our knowledge, no direct demonstration of any interplay between these phytochemicals and human primary amine oxidase (PrAO) has been reported to date. We took advantage of the coexistence of PrAO and monoamine oxidase (MAO) activities in human subcutaneous adipose tissue (hScAT) to test the interaction between several methylxanthines and these enzymes, which are involved in many key pathophysiological processes. Methods: Benzylamine, methylamine, and tyramine were used as substrates for PrAO and MAO in homogenates of subcutaneous adipose depots obtained from overweight women undergoing plastic surgery. Methylxanthines were tested as substrates or inhibitors by fluorimetric determination of hydrogen peroxide, an end-product of amine oxidation. Results: Semicarbazide-sensitive PrAO activity was inhibited by theobromine, caffeine, and isobutylmethylxanthine (IBMX) while theophylline, paraxanthine, and 7-methylxanthine had little effect. Theobromine inhibited PrAO activity by 54% at 2.5 mM. Overall, the relationship between methylxanthine structure and the degree of inhibition was similar to that seen with bovine PrAO, although higher concentrations (mM) were required for inhibition. Theobromine also inhibited oxidation of tyramine by MAO, at the limits of its solubility in a DMSO vehicle. At doses higher than 12 % v/v, DMSO impaired MAO activity. MAO was also inhibited by millimolar doses of IBMX, caffeine and by other methylxanthines to a lesser extent. Conclusions: This preclinical study extrapolates previous findings with bovine PrAO to human tissues. Given that PrAO is a potential target for anti-inflammatory drugs, it indicates that alongside phosphodiesterase inhibition and adenosine receptor antagonism, PrAO and MAO inhibition could contribute to the health benefits of methylxanthines, especially their anti-inflammatory effects.

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Section: Introductionmentioning

confidence: 99%

“…In mammals, PrAO is highly expressed at the surface of inflamed blood vessels, but also in vascular smooth muscles and in adipocytes [15,27]. In light of the relative accessibility of human subcutaneous adipose tissue and its high PrAO level [28], we performed inhibition studies on this human material.…”

Section: Introductionmentioning

confidence: 99%

Methylxanthines Inhibit Primary Amine Oxidase and Monoamine Oxidase Activities of Human Adipose Tissue

et al. 2020

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“…Vascular adhesion protein-1 (VAP-1) is a membrane-bound amine oxidase that, under normal physiological conditions, is expressed in vascular endothelial cells, smooth muscle cells, and adipocytes. 75 During homeostasis, VAP-1 is localized to cytoplasmic vesicles in endothelial cells, but under inflammatory conditions, the protein is trafficked to the cell surface. 76 Early studies of VAP-1 showed that it mediated leukocyte binding to high endothelial venules (HEVs), the specialized post-capillary venules found in lymph nodes.…”

Section: Atypical Adhesion Moleculesmentioning

confidence: 99%

“…81 Several preclinical studies targeting VAP-1 have confirmed that inhibition of its enzymatic activity and/or blockade of its adhesive function with therapeutic antibodies reduces leukocyte infiltration in a range of rodent models of inflammatory diseases. 82 Scavenger receptor that binds phosphatidylserine and oxidized lipids (SR-PSOX), which in its soluble form is also known as the chemokine, CXCL16, is expressed by LSEC 35 and is upregulated in both acutely 83,84 and chronically injured liver tissues. 85 CXCL16 is a specific ligand for the chemokine receptor CXCR6, thus enabling its membrane-bound form to interact with intrahepatic CXCR6 þ immune cells, such as effector T cells, 85,86 natural killer (NK) cells, 87,88 and NKT cells.…”

Section: Atypical Adhesion Moleculesmentioning

confidence: 99%

Novel Targets in the Immune Microenvironment of the Hepatic Sinusoids for Treating Liver Diseases

et al. 2019

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Immune dysregulation and accumulation of leukocytes is a hallmark of adult chronic liver diseases. Progressive hepatic inflammation can lead to fibrosis and cirrhosis with a high risk of liver failure or hepatocellular cancer (HCC). Recent advances have been made in the treatment of liver disease including the development of highly effective antiviral therapy for hepatitis C and the potential of immunotherapy for HCC. Despite this, the majority of other chronic liver diseases including alcoholic liver disease, fatty liver disease, and cholestatic diseases do not respond to conventional anti-inflammatory therapies. Recent studies defining the organ-specific properties that contribute to resident immune activation and immune cell recruitment from the circulation in these conditions have identified novel hepatic inflammatory pathways, which are now being targeted in clinical trials. Further understanding of how the immune microenvironment is regulated within the liver and how disease-specific mechanisms alter this process will hopefully lead to combination therapies to prevent aberrant inflammation and also promote fibrosis resolution. In this review, we focus on the advances that have been made in identifying key components of the inflammatory pathway including the recognition of danger signals, the recruitment and retention of lymphocytes from the circulation, and the pathways that promote resolution.

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“…VAP-1 is a multifunctional protein with amine oxidase activity that is found in adipocytes and endothelial cells. It supports leukocyte extravasation by enzyme-activity independent and dependent ways and has insulin-like effects on energy metabolism [15]. We have observed that the amine oxidase activity of VAP-1 was involved in bacterial lipopolysaccharide-induced inflammation model [16], but so far, it is unknown whether VAP-1 mediates the inflammatory effects of other bacterial surface molecules including FLG.…”

Section: Introductionmentioning

confidence: 94%

Vascular Adhesion Protein 1 Mediates Gut Microbial Flagellin-Induced Inflammation, Leukocyte Infiltration, and Hepatic Steatosis

Toivonen¹,

Vanhatalo²,

Hollmén³

et al. 2019

Sci

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Toll-like receptor 5 ligand, flagellin, and Vascular Adhesion Protein-1 (VAP-1) are involved in non-alcoholic fatty liver disease (NAFLD). This study aimed to determine whether VAP-1 mediates flagellin-induced hepatic fat accumulation. The effects of flagellin on adipocyte VAP-1 expression were first studied in vitro. Then, flagellin (100 ng/mouse) or saline was intraperitoneally injected to C57BL/6J WT and C57BL/6-Aoc3-/- (VAP-1 KO) mice on high-fat diet twice a week every two weeks for 10-weeks. After that, the effects on inflammation, insulin signaling, and metabolism were studied in liver and adipose tissues. Hepatic fat was quantified histologically and biochemically. Because flagellin challenge increased VAP-1 expression in human adipocytes, we used VAP-1 KO mice to determine whether VAP-1 regulates the inflammatory and metabolic effects of flagellin in vivo. In mice, VAP-1 mediated flagellin-induced inflammation, leukocyte infiltration and lipolysis in visceral adipose tissue. Consequently, increased release of glycerol led to hepatic steatosis in WT but not KO mice. Flagellin-induced hepatic fibrosis was not mediated by VAP-1. VAP-1 KO mice harbored more inflammation-related microbes than WT, while flagellin did not affect the gut microbiota. Our results suggest that by acting on visceral adipose tissue, flagellin increased leukocyte infiltration that induced lipolysis. Further, the released glycerol participated in hepatic fat accumulation. In conclusion, the results describe that gut microbial flagellin through VAP-1 induced hepatic steatosis.

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

Cited by 76 publications

References 149 publications

Methylxanthines Inhibit Primary Amine Oxidase and Monoamine Oxidase Activities of Human Adipose Tissue

Methylxanthines Inhibit Primary Amine Oxidase and Monoamine Oxidase Activities of Human Adipose Tissue

Novel Targets in the Immune Microenvironment of the Hepatic Sinusoids for Treating Liver Diseases

Vascular Adhesion Protein 1 Mediates Gut Microbial Flagellin-Induced Inflammation, Leukocyte Infiltration, and Hepatic Steatosis

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