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词条 AOC3
释义

  1. Structure

  2. Function

  3. Clinical significance

  4. Interactions

  5. References

  6. External links

  7. Further reading

{{Infobox_gene}}Amine oxidase, copper containing 3, also known as vascular adhesion protein (VAP-1) and HPAO is an enzyme that in humans is encoded by the AOC3 gene on chromosome 17. This protein is a member of the semicarbazide-sensitive amine oxidase (SSAO) family and is associated with many vascular diseases.[1]

Structure

VAP-1 is a type 1 membrane-bound glycoprotein that has a distal adhesion domain and an enzymatically active amine oxidase site outside of the membrane.[2][3] The AOC3 gene is mapped onto 17q21 and has an exon count of 6.[1]

Function

Amine oxidases are a family of enzymes that catalyze the oxidation of various endogenous amines, including histamine or dopamine. VAP-1 constitutes the copper dependent class of amine oxidases, such as lysyl oxidase or lysine demethylase, and is one of the four known in humans. The other class is flavin dependent such as monoamine oxidase (MAO) A and B.[1][4] VAP-1, in particular, catalyzes the oxidative conversion of primary amines (methylamine and aminoacetone) to aldehydes (formaldehyde and methylglyoxal) ammonium and hydrogen peroxide in the presence of copper and quinone cofactor.[4][5][6]

VAP-1 is primarily localized on the cell surface on the adipocyte plasma membrane.[1][7] However, circulating VAP-1 has been shown to be the main source of SSAO in human serum. Serum VAP-1 originates from many tissues.[7][8] VAP-1 has adhesive properties, functional monoamine oxidase activity, and possibly plays a role in glucose handling, leukocyte trafficking, and migration during inflammation.[1][5][9] This rise in metabolic products contributes to generating advanced glycation end-products and oxidative stress along with the monoamine detoxification in the organism.[7][10]

Like monoamine oxidase (MAO), VAP-1 can deaminate short-chain primary amines, but SSAO enzymes, including VAP-1, can tolerate several selective flavin-dependent MAO-A and MAO-B inhibitors like clorgiline, pargyline, and deprenyl, but are still sensitive to semicarbazide and other hydrazines, hydroxylamine and propargylamine.[1][11]

VAP-1 is found in the smooth muscle of blood vessels and various other tissues, and can mostly be found in two forms: tissue-bound and soluble isoforms.[5][11] The tissue-bound SSAO is primarily located in the leukocytes, adipocytes, and the endothelium of highly vascularized tissues, including the kidney, liver, and gonads.[5][12] Thus, this form participates in cellular differentiation, deposition of the ECM (extracellular matrix) in smooth muscle cells, lipid trafficking in adipocytes and control of muscular tone, by mechanisms that are not completely understood.[10][12] The soluble form, which is commonly known as VAP-1, is a proinflammatory protein derived from shedding of the transmembrane protein. It is highly expressed on the endothelium of the lung and trachea, and absent from leukocytes and epithelial cells. It moderates leukocyte recruitment, is both an adhesion molecule and a primary amine oxidase, and plays a role in clinical disease.[3][12][13][14]

Clinical significance

Membrane-bound VAP-1 releases an active, soluble form of the protein, which may be conducive to increased inflammation and the progression of many vascular disorders. In particular, elevation of VAP-1 activity and the increased enzymatic-mediated deamination is proposed to play a role in renal and vascular disease, oxidative stress, acute and chronic hyperglycemia, and diabetes complications.[1][8][9][15]

In diabetic patients, the amine oxidase activity stimulates glucose uptake via translocation of transporters to the cell membrane in adipocytes and smooth muscle cells. This modifies hepatic glucose homeostasis and may contribute to patterns of GLUT expression in chronic disease, as insulin resistance in humans have been linked to altered expression of GLUT isoforms by granulosa cells and adipose tissues.[16]

In particular, hydrogen peroxide, released during the deamination of SSAO, acts as a signal-transducing molecule, affecting GLUT1 and GLUT4 translocation to the plasma membrane by granulosa cells and adipose tissue.[3] This mimics insulin and interferes with cell processes in diabetic patients. Additionally, hydrogen peroxide, along with aldehydes and glucose, is involved in generating advanced glycation end-products and oxidative stress, which leads to the development of atherosclerosis, a disease in which plaque builds up inside arteries.[12]

Cell processes involved in insulin resistance are often associated with elevated VAP-1 expression and modified GLUT expression in patients with liver diseases.[8] Accordingly, subjects with diabetes are often at an increased risk for the development of and mortality from various cancers, including colorectal cancer hepatocellular carcinoma. Because of hyperinsulinemia - the increased bioavailability of insulin-like growth factors-1 and hypoadiponectinemia - diabetic patients have a greater chance of developing oncogenesis and tumor progression. In one study, serum VAP-1 was shown to independently predict 10-year all-cause mortality, cardiovascular mortality, and cancer-related mortality in subjects with type 2 diabetes.[16] This may be because VAP-1 is involved in binding TIL, lymphokine-activated killer cells, and natural killer cells to the vasculature of cancer tissue.[17] Hence, increased serum VAP-1 activity has been repeatedly found to be associated with various vascular disorders, such as the complications of diabetes mellitus, acute and chronic hyperglycemia, congestive heart failure, atherosclerosis, and Alzheimer's disease.[6][8]

The same elevation is seen in kidney disease, even when accounted for factors of age, gender, and smoking. Studies have established a strong correlation between serum VAP-1 levels and urinary albumin excretion, which supports the idea that VAP-1 may be involved in the pathogenesis of kidney damage in humans.[8][9][15][16] In renal pathology, the aldehydes produced by SSAO are highly reactive and lead to the formation of protein cross-linking and oxidative stress. Additionally, VAP-1 mediates leukocyte migration and, eventually, can lead to chronic inflammatory cell accumulation and the development of kidney fibrosis.[12]

As for stroke patients, the products from deamination induce cytotoxicity protein cross-linking and amyloid-beta (Aβ) aggregation along with oxidative stress and thus are considered a potential risk factor for stress-related angiopathy. In these patients, VAP-1 may be involved in increasing vascular damage due to increased susceptibility of endothelial cells to oxygen-glucose deprivation (OGD).[8][13] In hemorrhagic stroke patients, plasmatic VAP-1 activity is increase, and in ischemic stroke patients, it can predict the appearance of parenchymal hemorrhages after tissue plasminogen activator treatment due to the transmigration of inflammatory cells into ischaemic brain. VAP-1-expression is increased in blood vessels of ischemic areas where it may be mediating neutrophil adhesion to vascular endothelium in ischemic heart. The presence of diminished expression of vascular VAP-1 in infarcted brain areas and the increased concentration of VAP-1 in serum suggests that acute cerebral ischaemia triggers early release of endothelial VAP-1 from brain vasculature.[18]

Lastly, during pulmonary infection and airway hyper-activity,VAP-1 may also contribute to the recruitment of inflammatory cells and the transfer of neutrophils from the microvasculature.[4] Inhibitors of VAP-1 may be effective in reducing inflammation in various vascular diseases, but more studies are needed to understand to what extent.[1]

Whether serum VAP-1 is a good biomarker for these diseases requires further investigation.[19] Although many studies concerning VAP-1 as a therapeutic target are becoming more frequent, it is difficult to study VAP-1 in cell or tissue systems, since the enzyme progressively loses its expression, and immortalized cell lines do not show any expression at all.[10]

Interactions

VAP-1 has been shown to interact with:

  • MAO [11]

References

1. ^1 2 3 4 5 6 7 {{cite web | title = Entrez Gene: AOC3 Amine oxidase, copper containing 3 | url = https://www.ncbi.nlm.nih.gov/gene/8639| accessdate = }}
2. ^{{cite journal | vauthors = Foot JS, Yow TT, Schilter H, Buson A, Deodhar M, Findlay AD, Guo L, McDonald IA, Turner CI, Zhou W, Jarolimek W | title = PXS-4681A, a potent and selective mechanism-based inhibitor of SSAO/VAP-1 with anti-inflammatory effects in vivo | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 347 | issue = 2 | pages = 365–74 | date = Nov 2013 | pmid = 23943052 | doi = 10.1124/jpet.113.207613 }}
3. ^1 2 {{cite journal | vauthors = Schilter HC, Collison A, Russo RC, Foot JS, Yow TT, Vieira AT, Tavares LD, Mattes J, Teixeira MM, Jarolimek W | title = Effects of an anti-inflammatory VAP-1/SSAO inhibitor, PXS-4728A, on pulmonary neutrophil migration | journal = Respiratory Research | volume = 16 | pages = 42 | date = 20 March 2015 | pmid = 25889951 | doi = 10.1186/s12931-015-0200-z | pmc=4389443}}
4. ^1 2 {{cite journal | vauthors = Januszewski AS, Mason N, Karschimkus CS, Rowley KG, Best JD, O'Neal DN, Jenkins AJ | title = Plasma semicarbazide-sensitive amine oxidase activity in type 1 diabetes is related to vascular and renal function but not to glycaemia | journal = Diabetes & Vascular Disease Research | volume = 11 | issue = 4 | pages = 262–269 | date = May 2014 | pmid = 24853908 | doi = 10.1177/1479164114532963 }}
5. ^1 2 3 {{cite journal | vauthors = Repessé X, Moldes M, Muscat A, Vatier C, Chetrite G, Gille T, Planes C, Filip A, Mercier N, Duranteau J, Fève B | title = Hypoxia inhibits semicarbazide-sensitive amine oxidase activity in adipocytes | journal = Molecular and Cellular Endocrinology | volume = 411 | pages = 58–66 | date = Aug 2015 | pmid = 25907140 | doi = 10.1016/j.mce.2015.04.011 }}
6. ^1 {{cite journal | vauthors = Valente T, Gella A, Solé M, Durany N, Unzeta M | title = Immunohistochemical study of semicarbazide-sensitive amine oxidase/vascular adhesion protein-1 in the hippocampal vasculature: pathological synergy of Alzheimer's disease and diabetes mellitus | journal = Journal of Neuroscience Research | volume = 90 | issue = 10 | pages = 1989–96 | date = Oct 2012 | pmid = 22714978 | doi = 10.1002/jnr.23092 }}
7. ^1 2 {{cite journal | vauthors = Hernandez-Guillamon M, Solé M, Delgado P, García-Bonilla L, Giralt D, Boada C, Penalba A, García S, Flores A, Ribó M, Alvarez-Sabin J, Ortega-Aznar A, Unzeta M, Montaner J | title = VAP-1/SSAO plasma activity and brain expression in human hemorrhagic stroke | journal = Cerebrovascular Diseases | volume = 33 | issue = 1 | pages = 55–63 | date = 2012 | pmid = 22133888 | doi = 10.1159/000333370 }}
8. ^1 2 3 4 5 {{cite journal | vauthors = Li HY, Jiang YD, Chang TJ, Wei JN, Lin MS, Lin CH, Chiang FT, Shih SR, Hung CS, Hua CH, Smith DJ, Vanio J, Chuang LM | title = Serum vascular adhesion protein-1 predicts 10-year cardiovascular and cancer mortality in individuals with type 2 diabetes | journal = Diabetes | volume = 60 | issue = 3 | pages = 993–9 | date = Mar 2011 | pmid = 21282368 | doi = 10.2337/db10-0607 | pmc=3046860}}
9. ^1 2 {{cite journal | vauthors = Koc-Zorawska E, Przybylowski P, Malyszko JS, Mysliwiec M, Malyszko J | title = Vascular adhesion protein-1, a novel molecule, in kidney and heart allograft recipients | journal = Transplantation Proceedings | volume = 45 | issue = 5 | pages = 2009–12 | date = Jun 2013 | pmid = 23769096 | doi = 10.1016/j.transproceed.2013.01.103 }}
10. ^1 2 {{cite journal | vauthors = Solé M, Unzeta M | title = Vascular cell lines expressing SSAO/VAP-1: a new experimental tool to study its involvement in vascular diseases | journal = Biology of the Cell / Under the Auspices of the European Cell Biology Organization | volume = 103 | issue = 11 | pages = 543–57 | date = Nov 2011 | pmid = 21819380 | doi = 10.1042/BC20110049 }}
11. ^1 2 {{cite journal | vauthors = El-Maghrabey MH, Kishikawa N, Ohyama K, Imazato T, Ueki Y, Kuroda N | title = Determination of human serum semicarbazide-sensitive amine oxidase activity via flow injection analysis with fluorescence detection after online derivatization of the enzymatically produced benzaldehyde with 1,2-diaminoanthraquinone | journal = Analytica Chimica Acta | volume = 881 | pages = 139–47 | date = Jun 2015 | pmid = 26041530 | doi = 10.1016/j.aca.2015.04.006 }}
12. ^1 2 3 4 {{cite journal | vauthors = Wong M, Saad S, Zhang J, Gross S, Jarolimek W, Schilter H, Chen JA, Gill AJ, Pollock CA, Wong MG | title = Semicarbazide-sensitive amine oxidase (SSAO) inhibition ameliorates kidney fibrosis in a unilateral ureteral obstruction murine model | journal = American Journal of Physiology. Renal Physiology | volume = 307 | issue = 8 | pages = F908–16 | date = Oct 2014 | pmid = 25143459 | doi = 10.1152/ajprenal.00698.2013 }}
13. ^1 {{cite journal | vauthors = Sun P, Solé M, Unzeta M | title = Involvement of SSAO/VAP-1 in oxygen-glucose deprivation-mediated damage using the endothelial hSSAO/VAP-1-expressing cells as experimental model of cerebral ischemia | journal = Cerebrovascular Diseases | volume = 37 | issue = 3 | pages = 171–80 | date = 2014 | pmid = 24503888 | doi = 10.1159/000357660 }}
14. ^{{cite journal | vauthors = Weston CJ, Adams DH | title = Hepatic consequences of vascular adhesion protein-1 expression | journal = Journal of Neural Transmission | volume = 118 | issue = 7 | pages = 1055–64 | date = Jul 2011 | pmid = 21512782 | doi = 10.1007/s00702-011-0647-0 }}
15. ^1 {{cite journal | vauthors = Lin MS, Li HY, Wei JN, Lin CH, Smith DJ, Vainio J, Shih SR, Chen YH, Lin LC, Kao HL, Chuang LM, Chen MF | title = Serum vascular adhesion protein-1 is higher in subjects with early stages of chronic kidney disease | journal = Clinical Biochemistry | volume = 41 | issue = 16–17 | pages = 1362–7 | date = Nov 2008 | pmid = 18644360 | doi = 10.1016/j.clinbiochem.2008.06.019 }}
16. ^1 2 {{cite journal | vauthors = Karim S, Liaskou E, Fear J, Garg A, Reynolds G, Claridge L, Adams DH, Newsome PN, Lalor PF | title = Dysregulated hepatic expression of glucose transporters in chronic disease: contribution of semicarbazide-sensitive amine oxidase to hepatic glucose uptake | journal = American Journal of Physiology. Gastrointestinal and Liver Physiology | volume = 307 | issue = 12 | pages = G1180–90 | date = Dec 2014 | pmid = 25342050 | doi = 10.1152/ajpgi.00377.2013 | pmc=4269679}}
17. ^{{cite journal | vauthors = Kaplan MA, Kucukoner M, Inal A, Urakci Z, Evliyaoglu O, Firat U, Kaya M, Isikdogan A | title = Relationship between serum soluble vascular adhesion protein-1 level and gastric cancer prognosis | journal = Oncology Research and Treatment | volume = 37 | issue = 6 | pages = 340–4 | date = 2014 | pmid = 24903765 | doi = 10.1159/000362626 }}
18. ^{{cite journal | vauthors = Airas L, Lindsberg PJ, Karjalainen-Lindsberg ML, Mononen I, Kotisaari K, Smith DJ, Jalkanen S | title = Vascular adhesion protein-1 in human ischaemic stroke | journal = Neuropathology and Applied Neurobiology | volume = 34 | issue = 4 | pages = 394–402 | date = Aug 2008 | pmid = 18005095 | doi = 10.1111/j.1365-2990.2007.00911.x }}
19. ^{{cite journal | vauthors = Li HY, Wei JN, Lin MS, Smith DJ, Vainio J, Lin CH, Chiang FT, Shih SR, Huang CH, Wu MY, Hsein YC, Chuang LM | title = Serum vascular adhesion protein-1 is increased in acute and chronic hyperglycemia | journal = Clinica Chimica Acta; International Journal of Clinical Chemistry | volume = 404 | issue = 2 | pages = 149–53 | date = Jun 2009 | pmid = 19336232 | doi = 10.1016/j.cca.2009.03.041 }}

External links

  • {{UCSC gene info|AOC3}}

Further reading

{{refbegin|33em}}
  • {{cite journal | vauthors = Lalor PF, Lai WK, Curbishley SM, Shetty S, Adams DH | title = Human hepatic sinusoidal endothelial cells can be distinguished by expression of phenotypic markers related to their specialised functions in vivo | journal = World Journal of Gastroenterology | volume = 12 | issue = 34 | pages = 5429–39 | date = Sep 2006 | pmid = 17006978 | pmc = 4088223 | doi = 10.3748/wjg.v12.i34.5429 }}
  • {{cite journal | vauthors = Bustelo XR, Barbacid M | title = Tyrosine phosphorylation of the vav proto-oncogene product in activated B cells | journal = Science | volume = 256 | issue = 5060 | pages = 1196–9 | date = May 1992 | pmid = 1375396 | doi = 10.1126/science.256.5060.1196 }}
  • {{cite journal | vauthors = Andersson B, Wentland MA, Ricafrente JY, Liu W, Gibbs RA | title = A "double adaptor" method for improved shotgun library construction | journal = Analytical Biochemistry | volume = 236 | issue = 1 | pages = 107–13 | date = Apr 1996 | pmid = 8619474 | doi = 10.1006/abio.1996.0138 }}
  • {{cite journal | vauthors = Zhang X, McIntire WS | title = Cloning and sequencing of a copper-containing, topa quinone-containing monoamine oxidase from human placenta | journal = Gene | volume = 179 | issue = 2 | pages = 279–86 | date = Nov 1996 | pmid = 8972912 | doi = 10.1016/S0378-1119(96)00387-3 }}
  • {{cite journal | vauthors = Yu W, Andersson B, Worley KC, Muzny DM, Ding Y, Liu W, Ricafrente JY, Wentland MA, Lennon G, Gibbs RA | title = Large-scale concatenation cDNA sequencing | journal = Genome Research | volume = 7 | issue = 4 | pages = 353–8 | date = Apr 1997 | pmid = 9110174 | pmc = 139146 | doi = 10.1101/gr.7.4.353 }}
  • {{cite journal | vauthors = Smith DJ, Salmi M, Bono P, Hellman J, Leu T, Jalkanen S | title = Cloning of vascular adhesion protein 1 reveals a novel multifunctional adhesion molecule | journal = The Journal of Experimental Medicine | volume = 188 | issue = 1 | pages = 17–27 | date = Jul 1998 | pmid = 9653080 | pmc = 2525535 | doi = 10.1084/jem.188.1.17 }}
  • {{cite journal | vauthors = Lalor PF, Edwards S, McNab G, Salmi M, Jalkanen S, Adams DH | title = Vascular adhesion protein-1 mediates adhesion and transmigration of lymphocytes on human hepatic endothelial cells | journal = Journal of Immunology | volume = 169 | issue = 2 | pages = 983–92 | date = Jul 2002 | pmid = 12097405 | doi = 10.4049/jimmunol.169.2.983 }}
  • {{cite journal | vauthors = Salmi M, Stolen C, Jousilahti P, Yegutkin GG, Tapanainen P, Janatuinen T, Knip M, Jalkanen S, Salomaa V | title = Insulin-regulated increase of soluble vascular adhesion protein-1 in diabetes | journal = The American Journal of Pathology | volume = 161 | issue = 6 | pages = 2255–62 | date = Dec 2002 | pmid = 12466139 | pmc = 1850919 | doi = 10.1016/S0002-9440(10)64501-4 }}
  • {{cite journal | vauthors = Singh B, Tschernig T, van Griensven M, Fieguth A, Pabst R | title = Expression of vascular adhesion protein-1 in normal and inflamed mice lungs and normal human lungs | journal = Virchows Archiv | volume = 442 | issue = 5 | pages = 491–5 | date = May 2003 | pmid = 12700900 | doi = 10.1007/s00428-003-0802-6 }}
  • {{cite journal | vauthors = Zhang Q, Mashima Y, Noda S, Imamura Y, Kudoh J, Shimizu N, Nishiyama T, Umeda S, Oguchi Y, Tanaka Y, Iwata T | title = Characterization of AOC2 gene encoding a copper-binding amine oxidase expressed specifically in retina | journal = Gene | volume = 318 | issue = | pages = 45–53 | date = Oct 2003 | pmid = 14585497 | doi = 10.1016/S0378-1119(03)00753-4 }}
  • {{cite journal | vauthors = Conklin DJ, Cowley HR, Wiechmann RJ, Johnson GH, Trent MB, Boor PJ | title = Vasoactive effects of methylamine in isolated human blood vessels: role of semicarbazide-sensitive amine oxidase, formaldehyde, and hydrogen peroxide | journal = American Journal of Physiology. Heart and Circulatory Physiology | volume = 286 | issue = 2 | pages = H667–76 | date = Feb 2004 | pmid = 14715500 | doi = 10.1152/ajpheart.00690.2003 }}
  • {{cite journal | vauthors = Olivé M, Unzeta M, Moreno D, Ferrer I | title = Overexpression of semicarbazide-sensitive amine oxidase in human myopathies | journal = Muscle & Nerve | volume = 29 | issue = 2 | pages = 261–6 | date = Feb 2004 | pmid = 14755492 | doi = 10.1002/mus.10550 }}
  • {{cite journal | vauthors = Forster-Horváth C, Döme B, Paku S, Ladányi A, Somlai B, Jalkanen S, Tímár J | title = Loss of vascular adhesion protein-1 expression in intratumoral microvessels of human skin melanoma | journal = Melanoma Research | volume = 14 | issue = 2 | pages = 135–40 | date = Apr 2004 | pmid = 15057044 | doi = 10.1097/00008390-200404000-00010 }}
  • {{cite journal | vauthors = Aboulaich N, Vainonen JP, Strålfors P, Vener AV | title = Vectorial proteomics reveal targeting, phosphorylation and specific fragmentation of polymerase I and transcript release factor (PTRF) at the surface of caveolae in human adipocytes | journal = The Biochemical Journal | volume = 383 | issue = Pt 2 | pages = 237–48 | date = Oct 2004 | pmid = 15242332 | pmc = 1134064 | doi = 10.1042/BJ20040647 }}
  • {{cite journal | vauthors = Boomsma F, Pedersen-Bjergaard U, Agerholm-Larsen B, Hut H, Dhamrait SS, Thorsteinsson B, van den Meiracker AH | title = Association between plasma activities of semicarbazide-sensitive amine oxidase and angiotensin-converting enzyme in patients with type 1 diabetes mellitus | journal = Diabetologia | volume = 48 | issue = 5 | pages = 1002–7 | date = May 2005 | pmid = 15830186 | doi = 10.1007/s00125-005-1716-4 }}
  • {{cite journal | vauthors = Li HY, Lee WJ, Chen MJ, Chuang LM | title = Change in vascular adhesion protein-1 and metabolic phenotypes after vertical banded gastroplasty for morbid obesity | journal = Obesity Research | volume = 13 | issue = 5 | pages = 855–61 | date = May 2005 | pmid = 15919838 | doi = 10.1038/oby.2005.98 }}
  • {{cite journal | vauthors = Airenne TT, Nymalm Y, Kidron H, Smith DJ, Pihlavisto M, Salmi M, Jalkanen S, Johnson MS, Salminen TA | title = Crystal structure of the human vascular adhesion protein-1: unique structural features with functional implications | journal = Protein Science | volume = 14 | issue = 8 | pages = 1964–74 | date = Aug 2005 | pmid = 16046623 | pmc = 2279308 | doi = 10.1110/ps.051438105 }}
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