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Sirpa Jalkanen - One of the best experts on this subject based on the ideXlab platform.
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vascular Adhesion Protein 1 mediates gut microbial flagellin induced inflammation leukocyte infiltration and hepatic steatosis
Scientia Forestalis, 2021Co-Authors: Raine Toivonen, Sirpa Jalkanen, Sanja Vanhatalo, Maija Hollmen, Eveliina Munukka, Anniina Keskitalo, Sami Pietila, Laura L Elo, Pentti Huovinen, Satu PekkalaAbstract:Toll-like receptor 5 ligand, flagellin, and vascular Adhesion Protein 1 (VAP-1) are involved in non-alcoholic fatty liver disease. 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 into C57BL/6J (WT) and C57BL/6-Aoc3-/- (VAP-1 KO) mice on a high-fat diet twice a week every 2 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, an increased release of glycerol led to hepatic steatosis in WT, but not in KO mice. Flagellin-induced hepatic fibrosis was not mediated by VAP-1. VAP-1 KO mice harbored more inflammation-related microbes than WT mice, 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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Obesity of mice lacking VAP-1/SSAO by Aoc3 gene deletion is reproduced in mice expressing a mutated vascular Adhesion Protein-1 (VAP-1) devoid of amine oxidase activity
Journal of Physiology and Biochemistry, 2020Co-Authors: Valentin Jargaud, Sirpa Jalkanen, Sandy Bour, François Tercé, Xavier Collet, Philippe Valet, Anne Bouloumié, Jean-claude Guillemot, Pascale Mauriège, Craig StolenAbstract:The product of Aoc3 gene is known as vascular Adhesion Protein-1 (VAP-1), a glycoProtein contributing to leukocyte extravasation and exhibiting semicarbazide-sensitive amine oxidase activity (SSAO). Regarding the immune functions of VAP-1/SSAO, it is known that mice bearing Aoc3 gene knock-out (AOC3KO) exhibit defects in leukocyte migration similar to those of mice expressing a mutated VAP-1 lacking functional SSAO activity (knock-in, AOC3KI). However, it has not been reported whether these models differ regarding other disturbances. Thus, we further compared endocrine-metabolic phenotypes of AOC3KO and AOC3KI mice to their respective control. Special attention was paid on adiposity, glucose and lipid handling, since VAP-1/SSAO is highly expressed in adipose tissue (AT). In both mouse lines, no tissue SSAO activity was found, while Aoc3 mRNA was absent in AOC3KO only. Although food consumption was unchanged, both AOC3KO and AOC3KI mice were heavier and fatter than their respective controls. Other alterations commonly found in adipocytes from both lines were loss of benzylamine insulin-like action with unchanged insulin lipogenic responsiveness and adiponectin expression. A similar downregulation of inflammatory markers ( CD45 , IL6 ) was found in AT. Glucose handling and liver mass remained unchanged, while circulating lipid profile was distinctly altered, with increased cholesterol in AOC3KO only. These results suggest that the lack of oxidase activity found in AOC3KI is sufficient to reproduce the metabolic disturbances observed in AOC3KO mice, save those related with cholesterol transport. Modulation of SSAO activity therefore constitutes a potential target for the treatment of cardiometabolic diseases, especially obesity when complicated by low-grade inflammation.
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vascular Adhesion Protein 1 a cell surface amine oxidase in translation
Antioxidants & Redox Signaling, 2017Co-Authors: Marko Salmi, Sirpa JalkanenAbstract: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.
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vascular Adhesion Protein 1 a cell surface amine oxidase in translation
Antioxidants & Redox Signaling, 2017Co-Authors: Marko Salmi, Sirpa JalkanenAbstract: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 w...
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age sex and glucose dependent correlation of plasma soluble vascular Adhesion Protein 1 concentration with cardiovascular risk factors and subclinical atherosclerosis
European Review for Medical and Pharmacological Sciences, 2016Co-Authors: D W Chen, Sirpa Jalkanen, Y Jin, R Zhao, L Long, J Zhang, Chunlei Han, Anne Roivainen, Juhani Knuuti, J WangAbstract:OBJECTIVE Soluble vascular Adhesion Protein-1 (sVAP-1) may act as a biomarker for atherosclerosis and cardiovascular diseases. The associations of sVAP-1 concentration with cardiovascular risk factors and subclinical atherosclerosis at the population level have not been reported. PATIENTS AND METHODS This cross-sectional study included 834 asymptomatic subjects (49.1 ± 9.3 years). sVAP-1 was measured by enzyme-linked immunosorbent assay. Subclinical atherosclerosis was assessed by brachial-ankle pulse wave velocity (baPWV) and carotid intima-media thickness (CIMT). RESULTS sVAP-1 increased with age. Women had a higher concentration than men in age > 40 years. In women, sVAP-1 was negatively associated with estradiol (p 55 years. CONCLUSIONS sVAP-1 concentration correlates with cardiovascular risk factors and subclinical atherosclerosis in an age-, sex- and glucose-dependent manner.
Marko Salmi - One of the best experts on this subject based on the ideXlab platform.
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vascular Adhesion Protein 1 a cell surface amine oxidase in translation
Antioxidants & Redox Signaling, 2017Co-Authors: Marko Salmi, Sirpa JalkanenAbstract: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.
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vascular Adhesion Protein 1 a cell surface amine oxidase in translation
Antioxidants & Redox Signaling, 2017Co-Authors: Marko Salmi, Sirpa JalkanenAbstract: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 w...
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soluble vascular Adhesion Protein 1 predicts incident major adverse cardiovascular events and improves reclassification in a finnish prospective cohort study
Circulation-cardiovascular Genetics, 2014Co-Authors: Kristiina Aalto, Sirpa Jalkanen, Aki S Havulinna, Veikko Salomaa, Marko SalmiAbstract:Background—Vascular Adhesion Protein-1 (VAP-1) associates to subclinical atherosclerotic manifestations in young people, but its association to incident major adverse cardiovascular events (MACEs) ...
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Cloning of Vascular Adhesion Protein 1 Reveals a Novel Multifunctional Adhesion Molecule
2013Co-Authors: J. Smith, Marko Salmi, Petri Bono, Jukka Hellman, Taina Leu, Sirpa JalkanenAbstract:Vascular Adhesion Protein 1 (VAP-1) is a human endothelial sialoglycoProtein whose cell surface expression is induced under inflammatory conditions. It has been shown previously to participate in lymphocyte recirculation by mediating the binding of lymphocytes to peripheral lymph node vascular endothelial cells in an L-selectin–independent fashion. We report here that the VAP-1 cDNA encodes a type II transmembrane Protein of 84.6 kD with a single transmembrane domain located at the NH2-terminal end of the molecule and six potential N-glycosylation sites in the extracellular domain. In vivo, the Protein exists predominantly as a homodimer of 170–180 kD. Ax endothelial cells transfected with a VAP-1 cDNA express VAP-1 on their cell surface and bind lymphocytes, and the binding can be partially inhibited with anti–VAP-1 mAbs. VAP-1 has no similarity to any currently known Adhesion molecules, but has significant identity to the copper-containing amine oxidase family and has a monoamine oxidase activity. We propose that VAP-1 is a novel type of Adhesion molecule with dual function. With the appropriate glycosylation and in the correct inflammatory setting, its expression on the lumenal endothelial cell surface allows it to mediate lymphocyte Adhesion and to function as an Adhesion receptor involved in lymphocyte recirculation. Its primary function i
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regulation of mucosal addressin cell Adhesion molecule 1 expression in human and mice by vascular Adhesion Protein 1 amine oxidase activity
Hepatology, 2011Co-Authors: Evaggelia Liaskou, Sirpa Jalkanen, Marko Salmi, Christopher J Weston, Gary Reynolds, Patricia F Lalor, Marika Karikoski, Nicholas Pullen, David H AdamsAbstract:Primary sclerosing cholangitis (PSC) and autoimmune hepatitis are hepatic complications associated with inflammatory bowel disease (IBD). The expression of mucosal addressin cell Adhesion molecule 1 (MAdCAM-1) on mucosal endothelium is a prerequisite for the development of IBD, and it is also detected on the hepatic vessels of patients with liver diseases associated with IBD. This aberrant hepatic expression of MAdCAM-1 results in the recruitment of effector cells initially activated in the gut to the liver, in which they drive liver injury. However, the factors responsible for the aberrant hepatic expression of MAdCAM-1 are not known. In this study, we show that deamination of methylamine (MA) by vascular Adhesion Protein 1 (VAP-1) [a semicarbazide-sensitive amine oxidase (SSAO) expressed in the human liver] in the presence of tumor necrosis factor α induces the expression of functional MAdCAM-1 in hepatic endothelial cells and in intact human liver tissue ex vivo. This is associated with increased Adhesion of lymphocytes from patients with PSC to hepatic vessels. Feeding mice MA, a constituent of food and cigarette smoke found in portal blood, led to VAP-1/SSAO–dependent MAdCAM-1 expression in mucosal vessels in vivo. Conclusion: Activation of VAP-1/SSAO enzymatic activity by MA, a constituent of food and cigarette smoke, induces the expression of MAdCAM-1 in hepatic vessels and results in the enhanced recruitment of mucosal effector lymphocytes to the liver. This could be an important mechanism underlying the hepatic complications of IBD. (HEPATOLOGY 2011;53:661-672)
Bernard W Balleine - One of the best experts on this subject based on the ideXlab platform.
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inhibition of semicarbazide sensitive amine oxidase vascular Adhesion Protein 1 reduces lipopolysaccharide induced neuroinflammation
British Journal of Pharmacology, 2017Co-Authors: Serena Becchi, Alberto Buson, Jonathan S Foot, Wolfgang Jarolimek, Bernard W BalleineAbstract:Background and Purpose Neuroinflammation is initiated by a variety of stimuli including infections, sepsis, neurodegenerative diseases or traumatic brain injury and, if not adequately controlled, can lead to various degrees of neuronal damage and behavioural impairment. A critical event in the initial steps of inflammation is neutrophil extravasation. Semicarbazide-sensitive amine oxidase (SSAO, also known as vascular Adhesion Protein 1 or VAP-1) regulates neutrophil Adhesion and extravasation. Here, we elucidate the role of SSAO/VAP-1 in the early stage inflammatory response after LPS insult in the brain. Experimental Approach PXS-4681A, a selective and irreversible SSAO/VAP-1 inhibitor, was tested in two rat models of neuroinflammation, following systemic or i.c.v. LPS. Immunohistochemical and immunofluorescence techniques were used to measure neutrophils and microglia. VAP-1 was quantitated by Western blotting. Key Results Both systemic and i.c.v. administration of LPS induced an increase in neutrophil recruitment and microglial response in various brain areas including the substantia nigra and striatum. PXS-4681A produced a significant inhibition of neutrophil recruitment and extravasation after i.c.v. LPS injection and also reversed microglial cell recruitment and morphological changes to the level of the sham controls in both LPS models. Conclusions and Implications PXS-4681A acted as an effective anti-inflammatory agent after both systemic and i.c.v. LPS injections suggesting that SSAO/VAP-1 inhibition could be beneficial in the treatment of brain inflammation.
Ali Hafezimoghadam - One of the best experts on this subject based on the ideXlab platform.
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localization of vascular Adhesion Protein 1 vap 1 in the human eye
Experimental Eye Research, 2010Co-Authors: L Almulki, Kousuke Noda, Shintaro Nakao, Toshio Hisatomi, Kennard L Thomas, Ali HafezimoghadamAbstract:Recently we showed a critical role for Vascular Adhesion Protein-1 (VAP-1) in rodents during acute ocular inflammation, angiogenesis, and diabetic retinal leukostasis. However, the expression of VAP-1 in the human eye is unknown. VAP-1 localization was therefore investigated by immunohistochemistry. Five micrometer thick sections were generated from human ocular tissues embedded in paraffin. Sections were incubated overnight with primary mAbs against VAP-1 (5 microg/ml), smooth muscle actin (1 microg/ml), CD31 or isotype-matched IgG at 4 degrees C. Subsequently, a secondary mAb was used for 30 min at room temperature, followed by Dako Envision + HRP (AEC) System for signal detection. The stained sections were examined using light microscopy and the signal intensity was quantified by two evaluators and graded into 4 discrete categories. In all examined ocular tissues, VAP-1 staining was confined to the vasculature. VAP-1 labeling showed the highest intensity in both arteries and veins of neuronal tissues: retina and optic nerve, and the lowest intensity in the iris vasculature (p < 0.05). Scleral and choroidal vessels showed moderate staining for VAP-1. VAP-1 intensity was significantly higher in the arteries compared to veins (p < 0.05). Furthermore, VAP-1 staining in arteries colocalized with both CD31 and smooth muscle actin (sm-actin) staining, suggesting expression of VAP-1 in endothelial cells, smooth muscle cells or potentially pericytes. In conclusion, immunohistochemistry reveals constitutive expression of VAP-1 in human ocular tissues. VAP-1 expression is nearly exclusive to the vasculature with arteries showing significantly higher expression than veins. Furthermore, VAP-1 expression in the ocular vasculature is heterogeneous, with the vessels of the optic nerve and the retina showing highest expressions. These results characterize VAP-1 expression in human ocular tissues.
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vascular Adhesion Protein 1 regulates leukocyte transmigration rate in the retina during diabetes
Experimental Eye Research, 2009Co-Authors: Kousuke Noda, Shintaro Nakao, Souska Zandi, Verena Engelstadter, Yukihiko Mashima, Ali HafezimoghadamAbstract:Abstract Vascular Adhesion Protein-1 (VAP-1) is an endothelial Adhesion molecule that possesses semicarbazide-sensitive amine oxidase (SSAO) activity and is involved in leukocyte recruitment. Leukocyte Adhesion to retinal vessels is a predominant feature of experimentally induced diabetic retinopathy (DR). However, the role of VAP-1 in this process is unknown. Diabetes was induced by i.p. injection of Streptozotocin in Long–Evans rats. The specific inhibitor of VAP-1, UV-002, was administered by daily i.p. injections. The expression of VAP-1 mRNA in the retinal extracts of normal and diabetic animals was measured by real-time quantitative polymerase chain reaction (PCR). Firm leukocyte Adhesion was quantified in retinal flatmounts after intravascular staining with concanavalin A (ConA). Leukocyte transmigration rate was quantified by in vivo acridine orange leukocyte staining (AOLS). In diabetic rats, the rate of leukocyte transmigration into the retinal tissues of live animals was significantly increased, as determined by AOLS. When diabetic animals were treated with daily injections of the VAP-1 inhibitor (0.3 mg/kg), leukocyte transmigration rate was significantly reduced ( P
David H Adams - One of the best experts on this subject based on the ideXlab platform.
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regulation of mucosal addressin cell Adhesion molecule 1 expression in human and mice by vascular Adhesion Protein 1 amine oxidase activity
Hepatology, 2011Co-Authors: Evaggelia Liaskou, Sirpa Jalkanen, Marko Salmi, Christopher J Weston, Gary Reynolds, Patricia F Lalor, Marika Karikoski, Nicholas Pullen, David H AdamsAbstract:Primary sclerosing cholangitis (PSC) and autoimmune hepatitis are hepatic complications associated with inflammatory bowel disease (IBD). The expression of mucosal addressin cell Adhesion molecule 1 (MAdCAM-1) on mucosal endothelium is a prerequisite for the development of IBD, and it is also detected on the hepatic vessels of patients with liver diseases associated with IBD. This aberrant hepatic expression of MAdCAM-1 results in the recruitment of effector cells initially activated in the gut to the liver, in which they drive liver injury. However, the factors responsible for the aberrant hepatic expression of MAdCAM-1 are not known. In this study, we show that deamination of methylamine (MA) by vascular Adhesion Protein 1 (VAP-1) [a semicarbazide-sensitive amine oxidase (SSAO) expressed in the human liver] in the presence of tumor necrosis factor α induces the expression of functional MAdCAM-1 in hepatic endothelial cells and in intact human liver tissue ex vivo. This is associated with increased Adhesion of lymphocytes from patients with PSC to hepatic vessels. Feeding mice MA, a constituent of food and cigarette smoke found in portal blood, led to VAP-1/SSAO–dependent MAdCAM-1 expression in mucosal vessels in vivo. Conclusion: Activation of VAP-1/SSAO enzymatic activity by MA, a constituent of food and cigarette smoke, induces the expression of MAdCAM-1 in hepatic vessels and results in the enhanced recruitment of mucosal effector lymphocytes to the liver. This could be an important mechanism underlying the hepatic complications of IBD. (HEPATOLOGY 2011;53:661-672)
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vascular Adhesion Protein 1 mediates Adhesion and transmigration of lymphocytes on human hepatic endothelial cells
Journal of Immunology, 2002Co-Authors: Patricia F Lalor, Sirpa Jalkanen, Marko Salmi, Sarah Edwards, Gillian Mcnab, David H AdamsAbstract:Vascular Adhesion Protein-1 (VAP-1) is an amine oxidase and Adhesion receptor that is expressed by endothelium in the human liver. The hepatic sinusoids are perfused by blood at low flow rates, and sinusoidal endothelium lacks selectin expression and has low levels of CD31, suggesting that VAP-1 may play a specific role in lymphocyte recruitment to the liver. In support of this we now report the constitutive expression of VAP-1 on human hepatic sinusoidal endothelial cells (HSEC) in vitro and demonstrate that VAP-1 supports Adhesion and transmigration of lymphocytes across these cells under physiological shear stress. These are the first studies to report the function of VAP-1 on primary human endothelial cells. Under static conditions lymphocyte Adhesion to unstimulated HSEC was dependent on VAP-1 and ICAM-2, whereas Adhesion to TNF-α-stimulated HSEC was dependent on ICAM-1, VCAM-1, and VAP-1. Under conditions of flow, blocking VAP-1 reduced lymphocyte Adhesion to TNF-α-treated HSEC by 50% and significantly reduced the proportion of adherent lymphocytes that transmigrated across cytokine or LPS-activated endothelium. In addition, inhibition of the amine oxidase activity of VAP-1 reduced both Adhesion and transmigration of lymphocytes to a level similar to that seen with VAP-1 Ab. Thus, VAP-1 can support transendothelial migration as well as Adhesion, and both functions are dependent on its enzymatic activity. In the absence of selectins and CD31, VAP-1 may play a specific role in lymphocyte recruitment via hepatic sinusoidal endothelium. Moreover, since VAP-1 is induced on nonhepatic endothelium in response to inflammation, its ability to support lymphocyte transendothelial migration may be an important systemic function of VAP-1.