Angiogenesis critically sustains the progression of both physiological and pathological processes. Copper behaves as an obligatory co-factor throughout the angiogenic signalling cascades, so much so that a deficiency causes neovascularization to abate. Moreover, the progress of several angiogenic pathologies (e.g. diabetes, cardiac hypertrophy and ischaemia) can be tracked by measuring serum copper levels, which are being increasingly investigated as a useful prognostic marker. Accordingly, the therapeutic modulation of body copper has been proven effective in rescuing the pathological angiogenic dysfunctions underlying several disease states. Vascular copper transport systems profoundly influence the activation and execution of angiogenesis, acting as multi-functional regulators of apparently discrete pro-angiogenic pathways. This review concerns the complex relationship among copper-dependent angiogenic factors, copper transporters and common pathological conditions, with an unusual accent on the multi-faceted involvement of the proteins handling vascular copper. Functions regulated by the major copper transport proteins (CTR1 importer, ATP7A efflux pump and metallo-chaperones) include the modulation of endothelial migration and vascular superoxide, known to activate angiogenesis within a narrow concentration range. The potential contribution of prion protein, a controversial regulator of copper homeostasis, is discussed, even though its angiogenic involvement seems to be mainly associated with the modulation of endothelial motility and permeability.

1.
Jain RK: Molecular regulation of vessel maturation. Nat Med 2003;9:685-693.
2.
Risau W: Mechanisms of angiogenesis. Nature 1997;386:671-674.
3.
Folkman J: Angiogenesis: an organizing principle for drug discovery? Nat Rev Drug Discov 2007;6:273-286.
4.
Ishida S, Andreux P, Poitry-Yamate C, Auwerx J, Hanahan D: Bioavailable copper modulates oxidative phosphorylation and growth of tumors. Proc Natl Acad Sci USA 2013;110:19507-19512.
5.
Wang F, Jiao P, Qi M, Frezza M, Dou QP, Yan B: Turning tumor-promoting copper into an anti-cancer weapon via high-throughput chemistry. Curr Med Chem 2010;17:2685-2698.
6.
Hayashi M, Nishiya H, Chiba T, Endoh D, Kon Y, Okui T: Trientine, a copper-chelating agent, induced apoptosis in murine fibrosarcoma cells in vivo and in vitro. J Vet Med Sci 2007;69:137-142.
7.
Yoshiji H, Kuriyama S, Yoshii J, Ikenaka Y, Noguchi R, Yanase K, Namisaki T, Yamazaki M, Tsujinoue H, Imazu H, Fukui H: The copper-chelating agent, trientine, attenuates liver enzyme-altered preneoplastic lesions in rats by angiogenesis suppression. Oncol Rep 2003;10:1369-1373.
8.
Yoshii J, Yoshiji H, Kuriyama S, Ikenaka Y, Noguchi R, Okuda H, Tsujinoue H, Nakatani T, Kishida H, Nakae D, Gomez DE, De Lorenzo MS, Tejera AM, Fukui H: The copper-chelating agent, trientine, suppresses tumor development and angiogenesis in the murine hepatocellular carcinoma cells. Int J Cancer 2001;94:768-773.
9.
Tiwari M, Narayanan K, Thakar MB, Jagani HV, Rao JV: Biosynthesis and wound healing activity of copper nanoparticles. IET Nanobiotechnol 2014;8:230-237.
10.
Mirastschijski U, Martin A, Jorgensen LN, Sampson B, Ågren MS: Zinc, copper, and selenium tissue levels and their relation to subcutaneous abscess, minor surgery, and wound healing in humans. Biol Trace Elem Res 2013;153:76-83.
11.
Borkow G, Gabbay J, Dardik R, Eidelman AI, Lavie Y, Grunfeld Y, Ikher S, Huszar M, Zatcoff RC, Marikovsky M: Molecular mechanisms of enhanced wound healing by copper oxide-impregnated dressings. Wound Repair Regen 2010;18:266-275.
12.
Rakhmetova AA, Alekseeva TP, Bogoslovskaya OA, Leipunskii IO, Ol'khovskaya IP, Zhigach AN, Glushchenko NN: Wound-healing properties of copper nanoparticles as a function of physicochemical parameters. Nanotechnol Russia 2010;5:271-276.
13.
Cangul IT, Gul NY, Topal A, Yilmaz R: Evaluation of the effects of topical tripeptide-copper complex and zinc oxide on open-wound healing in rabbits. Vet Dermatol 2006;17:417-423.
14.
Hainaut P, Rolley N, Davies M, and Milner J: Modulation by copper of p53 conformation and sequence-specific DNA binding: role for Cu(II)/Cu(I) redox mechanism. Oncogene 1995;10:27-32.
15.
Sen CK, Khanna S, Venojarvi M, Trikha P, Ellison EC, Hunt TK, Roy S: Copper-induced vascular endothelial growth factor expression and wound healing. Am J Physiol Heart Circ Physiol 2002;282:H1821-H1827.
16.
Santos SC, Miguel C, Domingues I, Calado A, Zhu Z, Wu Y, Dias S: VEGF and VEGFR-2 (KDR) internalization is required for endothelial recovery during wound healing. Exp Cell Res 2007;313:1561-1574.
17.
Kong N, Lin K, Li H, Chang J: Synergy effects of copper and silicon ions on stimulation of vascularization by copper-doped calcium silicate. J Mater Chem B 2014;2:1100-1110.
18.
Stähli C, Muja N, Nazhat SN: Controlled copper ion release from phosphate-based glasses improves human umbilical vein endothelial cell survival in a reduced nutrient environment. Tissue Eng Part A 2013;19:548-557.
19.
Cattalini JP, Haro LA, Gorustovich AA, Boccaccini AR, Lucangioli SE, Mouriño VL: Novel Cu2+ Releasing Composite Films for Bone Tissue Engineering. Proceedings of XVIII Argentinian Congress on Biomedical Engineering (SABI), Mar del Plata, September 28-30, 2011.
20.
Gérard C, Bordeleau LJ, Barralet J, Doillon CJ: The stimulation of angiogenesis and collagen deposition by copper. Biomaterials 2010;31:824-831.
21.
Mamou F, May KS, Schipper MJ, Gill N, Kariapper MS, Nair BM, Brewer G, Normolle D, Khan MK: Tetrathiomolybdate blocks bFGF- but not VEGF-induced incipient angiogenesis in vitro. Anticancer Res 2006;26:1753-1758.
22.
Martin F, Linden T, Katschinski DM, Oehme F, Flamme I, Mukhopadhyay CK, Eckhardt K, Tröger J, Barth S, Camenisch G, Wenger RH: Copper-dependent activation of hypoxia-inducible factor (HIF)-1: implications for ceruloplasmin regulation. Blood 2005;105:4613-4619.
23.
Feng W, Ye F, Xue W, Zhou Z, Kang YJ: Copper regulation of hypoxia-inducible factor-1 activity. Mol Pharmacol 2009;75:174-182.
24.
Wang GL, Jiang BH, Rue EA, Semenza GL: Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA 1995;92:5510-5514.
25.
Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, von Kriegsheim A, Hebestreit HF, Mukherji M, Schofield CJ, Maxwell PH, Pugh CW, Ratcliffe PJ: Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 2001;292:468-472.
26.
Qiu L, Ding X, Zhang Z, Kang YJ: Copper is required for cobalt-induced transcriptional activity of hypoxia-inducible factor-1. J Pharmacol Exp Ther 2012;342:561-567.
27.
Jiang Y, Reynolds C, Xiao C, Feng W, Zhou Z, Rodriguez W, Tyagi SC, Eaton JW, Saari JT, Kang YJ: Dietary copper supplementation reverses hypertrophic cardiomyopathy induced by chronic pressure overload in mice. J Exp Med 2007;204:657-666.
28.
Mukhopadhyay CK, Mazumder B, Fox PL: Role of hypoxia-inducible factor-1 in transcriptional activation of ceruloplasmin by iron deficiency. J Biol Chem 2000;275:21048-21054.
29.
Raju KS, Alessandri G, Ziche M, Gullino PM: Ceruloplasmin, copper ions, and angiogenesis. J Natl Cancer Inst 1982;69:1183-1188.
30.
Boz A, Evliyaoğlu O, Yildirim M, Erkan N, Karaca B: The value of serum zinc, copper, ceruloplasmin levels in patients with gastrointestinal tract cancers. Turk J Gastroenterol 2005;16:81-84.
31.
Duyndam MC, Hulscher TM, Fontijn D, Pinedo HM, Boven E: Induction of vascular endothelial growth factor expression and hypoxia-inducible factor 1 alpha protein by the oxidative stressor arsenite. J Biol Chem 2001;276:48066-48076.
32.
Jayadeep A, Raveendran PK, Kannan S, Nalinakumari KR, Mathew B, Krishnan Nair M, Menon VP: Serum levels of copper, zinc, iron and ceruplasmin in oral leukoplakia and squamous cell carcinoma. Exp Clin Cancer Res 1997;16:295-300.
33.
Chan A, Wong F, Arumanayagam M: Serum ultrafiltrable copper, total copper and ceruloplasmin concentrations in gynaecological carcinomas. Ann Clin Biochem 1993;30:545-549.
34.
Lokamani I, Looi ML, Md Ali SA, Mohd Dali AZ, Ahmad Annuar MA, Jamal R: Gelsolin and ceruloplasmin as potential predictive biomarkers for cervical cancer by 2D-DIGE proteomics analysis. Pathol Oncol Res 2014;20:119-129.
35.
Palmer LA, Semenza GL, Stoler MH, Johns RA: Hypoxia induces type II NOS gene expression in pulmonary artery endothelial cells via HIF-1? Am J Physiol 1998;274(2 Pt 1): L212-L219.
36.
Demura Y, Ameshima S, Ishizaki T, Okamura S, Miyamori I, Matsukawa S: The activation of eNOS by copper ion (Cu2+) in human pulmonary arterial endothelial cells (HPAEC). Free Radic Biol Med 1998;25:314-320.
37.
Kishimoto T, Oguri T, Ueda D, Tada M: Copper enhances EDNO (endothelium-derived nitric oxide) activity by cultured human vascular endothelial cells. Hum Cell 1996;9:117-124.
38.
Schuschke DA, Falcone JC, Saari JT, Fleming JT, Percival SS, Young SA, Pass JM, Miller FN: Endothelial cell calcium mobilization to acetylcholine is attenuated in copper-deficient rats. Endothelium 2000;7:83-92.
39.
Cooke CL, Davidge ST: Endothelial-dependent vasodilation is reduced in mesenteric arteries from superoxide dismutase knockout mice. Cardiovasc Res 2003;60:635-642.
40.
Chiarugi A, Pitari GM, Costa R, Ferrante M, Villari L, Amico-Roxas M, Godfraind T, Bianchi A, Salomone S: Effect of prolonged incubation with copper on endothelium-dependent relaxation in rat isolated aorta. Br J Pharmacol 2002;136:1185-1193.
41.
Shukla N, Thompson CS, Angelini GD, Mikhailidis DP, Jeremy JY: Low micromolar concentrations of copper augment the impairment of endothelium-dependent relaxation of aortae from diabetic rabbits. Metabolism 2004;53:1315-1321.
42.
Schuschke DA, Percival SS, Saari JT, Miller FN: Relationship between dietary copper concentration and acetylcholine-induced vasodilation in the microcirculation of rats. Biofactors 1999;10:321-327.
43.
Gunnett CA, Heistad DD, Faraci FM: Interleukin-10 protects nitric oxide-dependent relaxation during diabetes: role of superoxide. Diabetes 2002;51:1931-1937.
44.
García CE, Kilcoyne CM, Cardillo C, Cannon RO 3rd, Quyyumi AA, Panza JA: Effect of copper-zinc superoxide dismutase on endothelium-dependent vasodilation in patients with essential hypertension. Hypertension 1995;26(6 Pt 1):863-868.
45.
Bache RJ: Coronary artery disease: regulation of coronary blood flow; in Willerson JT, Cohn JN, Wellens HJJ, Holmes DR Jr (eds): Cardiovascular Medicine. London, Springer, 2007, p 662.
46.
Lin S, Fagan KA, Li KX, Shaul PW, Cooper DM, Rodman DM: Sustained endothelial nitric-oxide synthase activation requires capacitative Ca2+ entry. J Biol Chem 2000;275:17979-17985.
47.
Demura Y, Ishizaki T, Ameshima S, Okamura S, Hayashi T, Matsukawa S, Miyamori I: The activation of nitric oxide synthase by copper ion is mediated by intracellular Ca2+ mobilization in human pulmonary arterial endothelial cells. Br J Pharmacol 1998;125:1180-1187.
48.
Danthuluri NR, Cybulsky MI, Brock TA: ACh-induced calcium transients in primary cultures of rabbit aortic endothelial cells. Am J Physiol 1988;255(6 Pt 2):H1549-H1553.
49.
Attinà TM, Oliver JJ, Malatino LS, Webb DJ: Contribution of the M3 muscarinic receptors to the vasodilator response to acetylcholine in the human forearm vascular bed. Br J Clin Pharmacol 2008;66:300-303.
50.
Walch L, Brink C, Norel X: The muscarinic receptor subtypes in human blood vessels. Therapie 2001;56:223-226.
51.
Kummer W, Haberberger R: Extrinsic and intrinsic cholinergic systems of the vascular wall. Eur J Morphol 1999;37:223-226.
52.
Schilling WP, Rajan L, Strobl-Jager E: Characterization of the bradykinin-stimulated calcium influx pathway of cultured vascular endothelial cells. Saturability, selectivity, and kinetics. J Biol Chem 1989;264:12838-12848.
53.
Li S, Xie H, Li S, Kang YJ: Copper stimulates growth of human umbilical vein endothelial cells in a vascular endothelial growth factor-independent pathway. Exp Biol Med (Maywood) 2012;237:77-82.
54.
Li QF, Ding XQ, Kang YJ: Copper promotion of angiogenesis in isolated rat aortic ring: role of vascular endothelial growth factor. J Nutr Biochem 2014;25:44-49.
55.
Landriscina M, Bagalá C, Mandinova A, Soldi R, Micucci I, Bellum S, Prudovsky I, Maciag T: Copper induces the assembly of a multiprotein aggregate implicated in the release of fibroblast growth factor 1 in response to stress. J Biol Chem 2001;276:25549-25557.
56.
La Mendola D, Farkas D, Bellia F, Magrì A, Travaglia A, Hansson Ö, Rizzarelli E: Probing the copper(II) binding features of angiogenin. Similarities and differences between an N-terminus peptide fragment and the recombinant human protein. Inorg Chem 2012;51:128-141.
57.
Soncin F, Guitton JD, Cartwright T, Badet J: Interaction of human angiogenin with copper modulates angiogenin binding to endothelial cells. Biochem Biophys Res Commun 1997;236:604-610.
58.
Badet J, Soncin F, Guitton JD, Lamare O, Cartwright T, Barritault D: Specific binding of angiogenin to calf pulmonary artery endothelial cells. Proc Natl Acad Sci USA 1989;86:8427-8431.
59.
Raju KS, Alessandri G, Gullino PM: Characterization of a chemoattractant for endothelium induced by angiogenesis effectors. Cancer Res 1984;44:1579-1584.
60.
Alessandri G, Raju K, Gullino PM: Angiogenesis in vivo and selective mobilization of capillary endothelium in vitro by heparin-copper complex. Microcirc Endothelium Lymphatics 1984;1:329-346.
61.
Zhao W, McCallum SA, Xiao Z, Zhang F, Linhardt RJ: Binding affinities of vascular endothelial growth factor (VEGF) for heparin-derived oligosaccharides. Biosci Rep 2012;32:71-81.
62.
Dougher AM, Wasserstrom H, Torley L, Shridaran L, Westdock P, Hileman RE, Fromm JR, Anderberg R, Lyman S, Linhardt RJ, Kaplan J, Terman BI: Identification of a heparin binding peptide on the extracellular domain of the KDR VEGF receptor. Growth Factors 1997;14:257-268.
63.
Gitay-Goren H, Soker S, Vlodavsky I, Neufeld G: The binding of vascular endothelial growth factor to its receptors is dependent on cell surface-associated heparin-like molecules. J Biol Chem 1992;267:6093-6098.
64.
Khorana AA, Sahni A, Altland OD, Francis CW: Heparin inhibition of endothelial cell proliferation and organization is dependent on molecular weight. Arterioscler Thromb Vasc Biol 2003;23:2110-2115.
65.
Kagan HM, Li W: Lysyl oxidase: properties, specificity, and biological roles inside and outside of the cell. J Cell Biochem 2003;88:660-672.
66.
Yunker CK, Golembieski W, Lemke N, Schultz CR, Cazacu S, Brodie C, Rempel SA: SPARC-induced increase in glioma matrix and decrease in vascularity are associated with reduced VEGF expression and secretion. Int J Cancer 2008;122:2735-2743.
67.
Kupprion C, Motamed K, Sage EH: SPARC (BM-40, osteonectin) inhibits the mitogenic effect of vascular endothelial growth factor on microvascular endothelial cells. J Biol Chem 1998;273:29635-29640.
68.
Lane TF, Iruela-Arispe ML, Johnson RS, Sage EH: SPARC is a source of copper-binding peptides that stimulate angiogenesis. J Cell Biol 1994;125:929-943.
69.
Pickart L: The human tri-peptide GHK and tissue remodeling. J Biomater Sci Polym Ed 2008;19:969-988.
70.
Siméon A, Wegrowski Y, Bontemps Y, Maquart FX: Expression of glycosaminoglycans and small proteoglycans in wounds: modulation by the tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu(2+). J Invest Dermatol 2000;115:962-968.
71.
Siméon A, Emonard H, Hornebeck W, Maquart FX: The tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu2+ stimulates matrix metalloproteinase-2 expression by fibroblast cultures. Life Sci 2000;67:2257-2265.
72.
Pollard JD, Quan S, Kang T, Koch RJ: Effects of copper tripeptide on the growth and expression of growth factors by normal and irradiated fibroblasts. Arch Facial Plast Surg 2005;7:27-31.
73.
Massey P, Patt LM, D'Aoust JC: The effects of glycyl-L-histidyl-L-lysine copper chelate on the healing of diabetic ulcers: a pilot study. Wounds 1992;4:21-28.
74.
Mulder GD, Patt LM, Sanders L, Rosenstock J, Altman MI, Hanley ME, Duncan GW: Enhanced healing of ulcers in patients with diabetes by topical treatment with glycyl-L-histidyl-L-lysine copper. Wound Repair Regen 1994;2:259-269.
75.
Araya M, Pizarro F, Olivares M, Arredondo M, Gonzáles M, Méndez M: Understanding copper homeostasis in humans and copper effects on health. Biol Res 2006;39:183-187.
76.
Rae TD, Schmidt PJ, Pufahl RA, Culotta VC, O'Halloran TV: Undetectable intracellular free copper: the requirement of a copper chaperone for superoxide dismutase. Science 1999;284:805-808.
77.
De Feo CJ, Aller SG, Siluvai GS, Blackburn NJ, Unger VM: Three dimensional structure of the human copper transporter hCTR1. Proc Natl Acad Sci USA 2009;106:4237-4242.
78.
Zhou B, Gitschier J: hCTR1: a human gene for copper uptake identified by complementation in yeast. Proc Natl Acad Sci USA 1997;94:7481-7486.
79.
Kidane TZ, Farhad R, Lee KJ, Santos A, Russo E, Linder MC: Uptake of copper from plasma proteins in cells where expression of CTR1 has been modulated. Biometals 2012;25:697-709.
80.
Wyman S, Simpson RJ, McKie AT, Sharp PA: Dcytb (Cybrd1) functions as both a ferric and a cupric reductase in vitro. FEBS Lett 2008;582:1901-1906.
81.
Eisses, JF, Kaplan JH: Molecular characterization of hCTR1, the human copper uptake protein. J Biol Chem 2002;277:29162-29171.
82.
Lee J, Pena MM, Nose Y, Thiele DJ: Biochemical characterization of the human copper transporter Ctr1. J Biol Chem 2002;277:4380-4387.
83.
Klomp AE, Tops BB, Van Denberg IE, Berger R, Klomp LW: Biochemical characterization and subcellular localization of human copper transporter 1 (hCTR1). Biochem J 2002;364 (Pt 2):497-505.
84.
Petris MJ, Smith K, Lee J, Thiele DJ: Copper-stimulated endocytosis and degradation of the human copper transporter, hCtr1. J Biol Chem 2003;278:9639-9646.
85.
Molloy SA, Kaplan JH: Copper-dependent recycling of hCTR1, the human high affinity copper transporter. J Biol Chem 2009;284:29704-29713.
86.
van den Berghe PV, Folmer DE, Malingré HE, van Beurden E, Klomp AE, van de Sluis B, Merkx M, Berger R, Klomp LW: Human copper transporter 2 is localized in late endosomes and lysosomes and facilitates cellular copper uptake. Biochem J 2007;407:49-59.
87.
Bertinato J, Swist E, Plouffe LJ, Brooks SP, L'abbé MR: Ctr2 is partially localized to the plasma membrane and stimulates copper uptake in COS-7 cells. Biochem J 2008;409:731-740.
88.
Gunshin H, Mackenzie B, Berger UV, Gunshin Y, Romero MF, Boron WF, Nussberger S, Gollan JL, Hediger MA: Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature 1997;388:482-488.
89.
Kishi F, Tabuchi M: Human natural resistance-associated macrophage protein 2: gene cloning and protein identification. Biochem Biophys Res Commun 1998;251:775-783.
90.
Gruenheid S, Cellier M, Vidal S, Gros P: Identification and characterization of a second mouse Nramp gene. Genomics 1995;25:514-525.
91.
Arredondo M, Muñoz P, Mura CV, Nùñez MT: DMT1, a physiologically relevant apical Cu1+ transporter of intestinal cells. Am J Physiol Cell Physiol 2003;284:C1525-C1530.
92.
Illing AC, Shawki A, Cunningham CL, Mackenzie B: Substrate profile and metal-ion selectivity of human divalent metal-ion transporter-1. J Biol Chem 2012;287:30485-30496.
93.
Klomp LW, Lin SJ, Yuan DS, Klausner RD, Culotta VC, Gitlin JD: Identification and functional expression of HAH1, a novel human gene involved in copper homeostasis. J Biol Chem 1997;272:9221-9226.
94.
Culotta VC, Klomp LW, Strain J, Casareno RL, Krems B, Gitlin JD: The copper chaperone for superoxide dismutase. J Biol Chem 1997;272:23469-23472.
95.
Cobine PA, Pierrel F, Leary SC, Sasarman F, Horng YC, Shoubridge EA, Winge DR: The P174L mutation in human Sco1 severely compromises Cox17-dependent metallation but does not impair copper binding. J Biol Chem 2006;281:12270-12276.
96.
Carr HS, Winge DR: Assembly of cytochrome c oxidase within the mitochondrion. Acc Chem Res 2003;36:309-316.
97.
Nielson KB, Atkin CL, Winge DR: Distinct metal-binding configurations in metallothionein. J Biol Chem 1985;260:5342-5350.
98.
Stillman MJ: Spectroscopic studies of copper and silver binding to metallothioneins. Met Based Drugs 1999;6:277-290.
99.
Durnam DM, Palmiter RD: Transcriptional regulation of the mouse metallothionein-I gene by heavy metals. J Biol Chem 1981;256:5712-5716.
100.
Ogra Y, Aoyama M, Suzuki KT: Protective role of metallothionein against copper depletion. Arch Biochem Biophys 2006;451:112-118.
101.
Banci L, Bertini I, Ciofi-Baffoni S, Kozyreva T, Zovo K, Palumaa P: Affinity gradients drive copper to cellular destinations. Nature 2010;465:645-648.
102.
Linz R, Lutsenko S: Copper-transporting ATPases ATP7A and ATP7B: cousins, not twins. J Bioenerg Biomembr 2007;39:403-407.
103.
Lutsenko S, Gupta A, Burkhead JL, Zuzel V: Cellular multitasking: the dual role of human Cu-ATPases in cofactor delivery and intracellular copper balance. Arch Biochem Biophys 2008;476:22-32.
104.
La Fontaine S, Mercer JFB: Trafficking of the copper-ATPases, ATP7A and ATP7B: role in copper homeostasis. Arch Biochem Biophys 2007;463:149-167.
105.
Zimnicka AM, Ivy K, Kaplan JH: Acquisition of dietary copper: a role for anion transporters in intestinal apical copper uptake. Am J Physiol Cell Physiol 2011;300:C588-C599.
106.
Kaplan JH, Lutsenko S: Copper transport in mammalian cells: special care for a metal with special needs. J Biol Chem 2009;284:25461-25465.
107.
Linder MC: Biochemistry of Copper. New York, Plenum Press, 1991.
108.
Brewer GJ: Wilson's disease; in Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J (eds): Harrison's Principles of Internal Medicine, ed 18. New York, McGraw-Hill, 2012, chapt 360.
109.
Murray RK, Jacob M, Varghese J: Plasma proteins and immunoglobulins; in Bender DA, Botham KM, Weil PA, Kennelly PJ, Murray RK, Rodwell VW (eds): Harper's Illustrated Biochemistry, ed 29. New York, McGraw-Hill, 2011, chapt 50.
110.
Omoto E, Tavassoli M: Purification and characterization of ceruloplasmin receptors. Trans Assoc Am Physicians 1989;102:170-175.
111.
Narayanan G, R BS, Vuyyuru H, Muthuvel B, Konerirajapuram Natrajan S: CTR1 silencing inhibits angiogenesis by limiting copper entry into endothelial cells. PLoS One 2013;8:e71982.
112.
Gybina AA, Prohaska JR: Variable response of selected cuproproteins in rat choroid plexus and cerebellum following perinatal copper deficiency. Genes Nutr 2006;1:51-59.
113.
Kuo YM, Gybina AA, Pyatskowit JW, Gitschier J, Prohaska JR: Copper transport protein (Ctr1) levels in mice are tissue specific and dependent on copper status. J Nutr 2006;136:21-26.
114.
Choi BS, Zheng W: Copper transport to the brain by the blood-brain barrier and blood-CSF barrier. Brain Res 2009;1248:14-21.
115.
Holzer AK, Manorek GH, Howell SB: Contribution of the major copper influx transporter CTR1 to the cellular accumulation of cisplatin, carboplatin, and oxaliplatin. Mol Pharmacol 2006;70:1390-1394.
116.
Hardman B, Manuelpillai U, Wallace EM, Monty JF, Kramer DR, Kuo YM, Mercer JF, Ackland ML: Expression, localisation and hormone regulation of the human copper transporter hCTR1 in placenta and choriocarcinoma Jeg-3 cells. Placenta 2006;27:968-977.
117.
Zimnicka AM, Tang H, Guo Q, Kuhr FK, Oh MJ, Wan J, Chen J, Smith KA, Fraidenburg DR, Choudhury MS, Levitan I, Machado RF, Kaplan JH, Yuan JX: Upregulated copper transporters in hypoxia-induced pulmonary hypertension. PLoS One 2014;9:e90544.
118.
Ashino T, Sudhahar V, Urao N, Oshikawa J, Chen GF, Wang H, Huo Y, Finney L, Vogt S, McKinney RD, Maryon EB, Kaplan JH, Ushio-Fukai M, Fukai T: Unexpected role of the copper transporter ATP7A in PDGF-induced vascular smooth muscle cell migration. Circ Res 2010;107:787-799.
119.
White C, Lee J, Kambe T, Fritsche K, Petris MJ: A role for the ATP7A copper-transporting ATPase in macrophage bactericidal activity. J Biol Chem 2009;284:33949-33956.
120.
Sunderkötter C, Steinbrink K, Goebeler M, Bhardwaj R, Sorg C: Macrophages and angiogenesis. J Leukoc Biol 1994;55:410-422.
121.
Lee HW, Choi HJ, Ha SJ, Lee KT, Kwon YG: Recruitment of monocytes/macrophages in different tumor microenvironments. Biochim Biophys Acta 2013;1835:170-179.
122.
Squadrito ML, De Palma M: Macrophage regulation of tumor angiogenesis: implications for cancer therapy. Mol Aspects Med 2011;32:123-145.
123.
De Palma M, Naldini L: Tie2-expressing monocytes (TEMs): novel targets and vehicles of anticancer therapy? Biochim Biophys Acta 2009;1796:5-10.
124.
Joyce JA, Pollard JW: Microenvironmental regulation of metastasis. Nat Rev Cancer 2009;9:239-252.
125.
White C, Kambe T, Fulcher YG, Sachdev SW, Bush AI, Fritsche K, Lee J, Quinn TP, Petris MJ: Copper transport into the secretory pathway is regulated by oxygen in macrophages. J Cell Sci 2009;122(Pt 9):1315-1321.
126.
Zhang S, Liu H, Amarsingh GV, Cheung CC, Hogl S, Narayanan U, Zhang L, McHarg S, Xu J, Gong D, Kennedy J, Barry B, Choong YS, Phillips AR, Cooper GJ: Diabetic cardiomyopathy is associated with defective myocellular copper regulation and both defects are rectified by divalent copper chelation. Cardiovasc Diabetol 2014;13:100-117.
127.
Blair BG, Larson CA, Adams PL, Abada PB, Pesce CE, Safaei R, Howell SB: Copper transporter 2 regulates endocytosis and controls tumor growth and sensitivity to cisplatin in vivo. Mol Pharmacol 2011;79:157-166.
128.
Burdo JR, Menzies SL, Simpson IA, Garrick LM, Garrick MD, Dolan KG, Haile DJ, Beard JL, Connor JR: Distribution of divalent metal transporter 1 and metal transport protein 1 in the normal and Belgrade rat. J Neurosci Res 2001;66:1198-1207.
129.
Du F, Qian ZM, Luo Q, Yung WH, Ke Y: Hepcidin suppresses brain iron accumulation by downregulating iron transport proteins in iron-overloaded rats. Mol Neurobiol 2015;52:101-114.
130.
Nanami M, Ookawara T, Otaki Y, Ito K, Moriguchi R, Miyagawa K, Hasuike Y, Izumi M, Eguchi H, Suzuki K, Nakanishi T: Tumor necrosis factor-alpha-induced iron sequestration and oxidative stress in human endothelial cells. Arterioscler Thromb Vasc Biol 2005;25:2495-2501.
131.
Moos T, Skjoerringe T, Gosk S, Morgan EH: Brain capillary endothelial cells mediate iron transport into the brain by segregating iron from transferrin without the involvement of divalent metal transporter 1. J Neurochem 2006;98:1946-19458.
132.
Moos T, Morgan EH: The significance of the mutated divalent metal transporter (DMT1) on iron transport into the Belgrade rat brain. J Neurochem 2004;88:233-245.
133.
Moos T, Rosengren-Nielsen T: Ferroportin in the postnatal rat brain: implications for axonal transport and neuronal export of iron. Semin Pediatr Neurol 2006;13:49-57.
134.
Kim HW, Chan Q, Afton SE, Caruso JA, Lai B, Weintraub NL, Qin Z: Human macrophage ATP7A is localized in the trans-Golgi apparatus, controls intracellular copper levels, and mediates macrophage responses to dermal wounds. Inflammation 2012;35:167-175.
135.
Qin Z, Itoh S, Jeney V, Ushio-Fukai M, Fukai T: Essential role for the Menkes ATPase in activation of extracellular superoxide dismutase: implication for vascular oxidative stress. FASEB J 2006;20:334-336.
136.
Afton SE, Caruso JA, Britigan BE, Qin Z: Copper egress is induced by PMA in human THP-1 monocytic cell line. Biometals 2009;22:531-539.
137.
Hicks JD, Donsante A, Pierson TM, Gillespie MJ, Chou DE, Kaler SG: Increased frequency of congenital heart defects in Menkes disease. Clin Dysmorphol 2012;21:59-63.
138.
Hardman B, Luff S, Ackland ML: Differential intracellular localisation of the Menkes and Wilson copper transporting ATPases in the third trimester human placenta. Placenta 2011;32:79-85.
139.
Li SM, Zeng LW, Feng L, Chen DB: Rac1-dependent intracellular superoxide formation mediates vascular endothelial growth factor-induced placental angiogenesis in vitro. Endocrinology 2010;151:5315-5325.
140.
Finney L, Mandava S, Ursos L, Zhang W, Rodi D, Vogt S, Legnini D, Maser J, Ikpatt F, Olopade OI, Glesne D: X-ray fluorescence microscopy reveals large-scale relocalization and extracellular translocation of cellular copper during angiogenesis. Proc Natl Acad Sci USA 2007;104:2247-2252.
141.
Qin Z, Gongora MC, Ozumi K, Itoh S, Akram K, Ushio-Fukai M, Harrison DG, Fukai T: Role of Menkes ATPase in angiotensin II-induced hypertension: a key modulator for extracellular superoxide dismutase function. Hypertension 2008;52:945-951.
142.
Ozumi K, Sudhahar V, Kim HW, Chen GF, Kohno T, Finney L, Vogt S, McKinney RD, Ushio-Fukai M, Fukai T: Role of copper transport protein antioxidant 1 in angiotensin II-induced hypertension: a key regulator of extracellular superoxide dismutase. Hypertension 2012;60:476-486.
143.
Sudhahar V, Urao N, Oshikawa J, McKinney RD, Llanos RM, Mercer JF, Ushio-Fukai M, Fukai T: Copper transporter ATP7A protects against endothelial dysfunction in type 1 diabetic mice by regulating extracellular superoxide dismutase. Diabetes 2013;62:3839-3850.
144.
Bir SC, Shen X, Kavanagh TJ, Kevil CG, Pattillo CB: Control of angiogenesis dictated by picomolar superoxide levels. Free Radic Biol Med 2013;63:135-142.
145.
Chang M, Bany-Mohammed F, Kenney MC, Beharry KD: Effects of a superoxide dismutase mimetic on biomarkers of lung angiogenesis and alveolarization during hyperoxia with intermittent hypoxia. Am J Transl Res 2013;5:594-607.
146.
Chen JX, Zeng H, Lawrence ML, Blackwell TS, Meyrick B: Angiopoietin-1-induced angiogenesis is modulated by endothelial NADPH oxidase. Am J Physiol Heart Circ Physiol 2006;291:H1563-H1572.
147.
Nakao T, Morita H, Maemura K, Amiya E, Inajima T, Saito Y, Watanabe M, Manabe I, Kurabayashi M, Nagai R, Komuro I: Melatonin ameliorates angiotensin II-induced vascular endothelial damage via its antioxidative properties. J Pineal Res 2013;55:287-293.
148.
Chen F, Qian LH, Deng B, Liu ZM, Zhao Y, Le YY: Resveratrol protects vascular endothelial cells from high glucose-induced apoptosis through inhibition of NADPH oxidase activation-driven oxidative stress. CNS Neurosci Ther 2013;19:675-681.
149.
Hung MW, Kravtsov GM, Lau CF, Poon AM, Tipoe GL, Fung ML: Melatonin ameliorates endothelial dysfunction, vascular inflammation, and systemic hypertension in rats with chronic intermittent hypoxia. J Pineal Res 2013;55:247-256.
150.
Patel OV, Wilson WB, Qin Z: Production of LPS-induced inflammatory mediators in murine peritoneal macrophages: neocuproine as a broad inhibitor and ATP7A as a selective regulator. Biometals 2013;26:415-425.
151.
Rami L, Auguste P, Thebaud NB, Bareille R, Daculsi R, Ripoche J, Bordenave L: IQ domain GTPase-activating protein 1 is involved in shear stress-induced progenitor-derived endothelial cell alignment. PLoS One 2013;8:e79919.
152.
Chen G-F, Urao N, McKinney R, Ushio-Fukai M, Fukai T: Copper transporter ATP7A is involved in post-ischemic neovascularization by regulating endothelial junctional integrity through binding to IQGAP1. Circulation 2011;124:A13384.
153.
Yamaoka-Tojo M, Ushio-Fukai M, Hilenski L, Dikalov SI, Chen YE, Tojo T, Fukai T, Fujimoto M, Patrushev NA, Wang N, Kontos CD, Bloom GS, Alexander RW: IQGAP1, a novel vascular endothelial growth factor receptor binding protein, is involved in reactive oxygen species-dependent endothelial migration and proliferation. Circ Res 2004;95:276-283.
154.
Ma J, Xue Y, Liu W, Yue C, Bi F, Xu J, Zhang J, Li Y, Zhong C, Chen Y: Role of activated Rac1/Cdc42 in mediating endothelial cell proliferation and tumor angiogenesis in breast cancer. PLoS One 2013;8:e66275.
155.
Zhan H, Liang H, Liu X, Deng J, Wang B, Hao X: Expression of Rac1, HIF-1α, and VEGF in gastric carcinoma: correlation with angiogenesis and prognosis. Onkologie 2013;36:102-107.
156.
Hoang MV, Nagy JA, Senger DR: Active Rac1 improves pathologic VEGF neovessel architecture and reduces vascular leak: mechanistic similarities with angiopoietin-1. Blood 2011;117:1751-1760.
157.
Xue Y, Bi F, Zhang X, Zhang S, Pan Y, Liu N, Shi Y, Yao X, Zheng Y, Fan D: Role of Rac1 and Cdc42 in hypoxia induced p53 and von Hippel-Lindau suppression and HIF1alpha activation. Int J Cancer 2006;118:2965-2972.
158.
Ribatti D, Alessandri G, Baronio M, Raffaghello L, Cosimo E, Marimpietri D, Montaldo PG, De Falco G, Caruso A, Vacca A, Ponzoni M: Inhibition of neuroblastoma-induced angiogenesis by fenretinide. Int J Cancer 2001;94:314-321.
159.
Bohlken A, Cheung BB, Bell JL, Koach J, Smith S, Sekyere E, Thomas W, Norris M, Haber M, Lovejoy DB, Richardson DR, Marshall GM: ATP7A is a novel target of retinoic acid receptor beta2 in neuroblastoma cells. Br J Cancer 2009;100:96-105.
160.
Dong D, Xu X, Yin W, Kang YJ: Changes in copper concentrations affect the protein levels but not the mRNA levels of copper chaperones in human umbilical vein endothelial cells. Metallomics 2014;6:554-559.
161.
Brosel S, Yang H, Tanji K, Bonilla E, Schon EA: Unexpected vascular enrichment of SCO1 over SCO2 in mammalian tissues: implications for human mitochondrial disease. Am J Pathol 2010;177:2541-2548.
162.
Casareno RL, Waggoner D, Gitlin JD: The copper chaperone CCS directly interacts with copper/zinc superoxide dismutase. J Biol Chem 1998;273:23625-23628.
163.
Wang B, Dong D, Kang YJ: Copper chaperone for superoxide dismutase-1 transfers copper to mitochondria but does not affect cytochrome c oxidase activity. Exp Biol Med (Maywood) 2013;238:1017-1023.
164.
Chen G-F, Urao N, Mckinney R, Ushio-Fukai M, Fukai T: Antioxidant-1, a novel transcription factor for NADPH oxidase organizer p47phox, regulates postnatal neovascularization by modulating hydrogen peroxide production. Circulation 2011;124: A13501.
165.
Kim HW, Ozumi K, Ronald MD, Itoh S, Yang J, Nakagawa O, Lessner S, Ushio Fukai M, Fukai T: Novel role of copper-dependent transcription factor antioxidant-1 in cell proliferation and wound healing. Circulation 2007;116:II_197.
166.
Kawamata H, Manfredi G: Import, maturation, and function of SOD1 and its copper chaperone CCS in the mitochondrial intermembrane space. Antioxid Redox Signal 2010;13:1375-1384.
167.
Carroll MC, Girouard JB, Ulloa JL, Subramaniam JR, Wong PC, Valentine JS, Culotta VC: Mechanisms for activating Cu- and Zn-containing superoxide dismutase in the absence of the CCS Cu chaperone. Proc Natl Acad Sci USA 2004;101:5964-5969.
168.
Freedman JH, Ciriolo MR, Peisach J: The role of glutathione in copper metabolism and toxicity. J Biol Chem 1989;264:5598-5605.
169.
Maryon EB, Molloy SA, Kaplan JH: Cellular glutathione plays a key role in copper uptake mediated by human copper transporter 1. Am J Physiol Cell Physiol 2013;304:C768-C779.
170.
Ferreira AM, Ciriolo MR, Marcocci L, Rotilio G: Copper (I) transfer into metallothionein mediated by glutathione. Biochem J 1993;292:673-676.
171.
Nijmeh J, Moldobaeva A, Wagner EM: Role of ROS in ischemia-induced lung angiogenesis. Am J Physiol Lung Cell Mol Physiol 2010;299:L535-L541.
172.
Langston W, Chidlow JH Jr, Booth BA, Barlow SC, Lefer DJ, Patel RP, Kevil CG: Regulation of endothelial glutathione by ICAM-1 governs VEGF-A-mediated eNOS activity and angiogenesis. Free Radic Biol Med 2007;42:720-729.
173.
Kevil CG, Pruitt H, Kavanagh T, Wilkerson J, Farin F, Moellering D, Darley-Usmar V, Bullard D, Patel R: Regulation of endothelial glutathione by ICAM-1: implications for inflammation. FASEB J 2004;18:1321-1323.
174.
Miyayama T, Hiraoka D, Kawaji F, Nakamura E, Suzuki N, Ogra Y: Roles of COMM-domain-containing 1 in stability and recruitment of the copper-transporting ATPase in a mouse hepatoma cell line. Biochem J 2010;429:53-61.
175.
de Bie P, van de Sluis B, Burstein E, van de Berghe PV, Muller P, Berger R, Gitlin JD, Wijmenga C, Klomp LW: Distinct Wilson's disease mutations in ATP7B are associated with enhanced binding to COMMD1 and reduced stability of ATP7B. Gastroenterology 2007;133:1316-1326.
176.
Vonk WI, Bartuzi P, de Bie P, Kloosterhuis N, Wichers CG, Berger R, Haywood S, Klomp LW, Wijmenga C, van de Sluis B: Liver-specific Commd1 knockout mice are susceptible to hepatic copper accumulation. PLoS One 2011;6:e29183.
177.
Donadio S, Alfaidy N, De Keukeleire B, Micoud J, Feige JJ, Challis JR, Benharouga M: Expression and localization of cellular prion and COMMD1 proteins in human placenta throughout pregnancy. Placenta 2007;28:907-911.
178.
van de Sluis B, Muller P, Duran K, Chen A, Groot AJ, Klomp LW, Liu PP, Wijmenga C: Increased activity of hypoxia-inducible factor 1 is associated with early embryonic lethality in Commd1 null mice. Mol Cell Biol 2007;27:4142-4156.
179.
Kwon HS, Park SH, Hwang HS, Sohn IS, Kim SN: Expression and localization of COMMD1 proteins in human placentas from women with preeclampsia. Yonsei Med J 2013;54:494-499.
180.
van de Sluis B, Mao X, Zhai Y, Groot AJ, Vermeulen JF, van der Wall E, van Diest PJ, Hofker MH, Wijmenga C, Klomp LW, Cho KR, Fearon ER, Vooijs M, Burstein E: COMMD1 disrupts HIF-1alpha/beta dimerization and inhibits human tumor cell invasion. J Clin Invest 2010;120:2119-2130.
181.
Taylor DR, Watt NT, Perera WS, Hooper NM: Assigning functions to distinct regions of the N-terminus of the prion protein that are involved in its copper-stimulated, clathrin-dependent endocytosis. J Cell Sci 2005;118(Pt 21):5141-5153.
182.
Harris DA: Trafficking, turnover and membrane topology of PrP. Br Med Bull 2003;66:71-85.
183.
Prusiner SB: Biology and genetics of prions causing neurodegeneration. Annu Rev Genet 2013;47:601-623.
184.
Prusiner SB: Prions. Proc Natl Acad Sci USA 1998;95:13363-13383.
185.
Hornshaw MP, McDermott JR, Candy JM, Lakey JH: Copper binding to the N-terminal tandem repeat region of mammalian and avian prion protein: structural studies using synthetic peptides. Biochem Biophys Res Commun 1995;214:993-999.
186.
Hornshaw MP, McDermott JR, Candy JM: Copper binding to the N-terminal tandem repeat regions of mammalian and avian prion protein. Biochem Biophys Res Commun 1995;207:621-629.
187.
Millhauser GL: Copper and the prion protein: methods, structures, function, and disease. Annu Rev Phys Chem 2007;58:299-320.
188.
Vassallo N, Herms J: Cellular prion protein function in copper homeostasis and redox signalling at the synapse. J Neurochem 2003;86:538-544.
189.
Brown DR, Wong BS, Hafiz F, Clive C, Haswell SJ, Jones IM: Normal prion protein has an activity like that of superoxide dismutase. Biochem J 1999;344(Pt 1):1-5.
190.
Urso E, Manno D, Serra A, Buccolieri A, Rizzello A, Danieli A, Acierno R, Salvato B, Maffia M: Role of the cellular prion protein in the neuron adaptation strategy to copper deficiency. Cell Mol Neurobiol 2012;32:989-1001.
191.
Urso E, Rizzello A, Acierno R, Lionetto MG, Salvato B, Storelli C, Maffia M: Fluorimetric analysis of copper transport mechanisms in the B104 neuroblastoma cell model: a contribution from cellular prion protein to copper supplying. J Membr Biol 2010;233:13-21.
192.
Kramer ML, Kratzin HD, Schmidt B, Römer A, Windl O, Liemann S, Hornemann S, Kretzschmar H: Prion protein binds copper within the physiological concentration range. J Biol Chem 2001;276:16711-16719.
193.
Viles JH, Cohen FE, Prusiner SB, Goodin DB, Wright PE, Dyson HJ: Copper binding to the prion protein: structural implications of four identical cooperative binding sites. Proc Natl Acad Sci USA 1999;96:2042-2047.
194.
Brown DR, Qin K, Herms JW, Madlung A, Manson J, Strome R, Fraser PE, Kruck T, von Bohlen A, Schulz-Schaeffer W, Giese A, Westaway D, Kretzschmar H: The cellular prion protein binds copper in vivo. Nature 1997;390:684-687.
195.
Pauly PC, Harris DA: Copper stimulates endocytosis of the prion protein. J Biol Chem 1998;273:33107-33110.
196.
Simák J, Holada K, D'Agnillo F, Janota J, Vostal JG: Cellular prion protein is expressed on endothelial cells and is released during apoptosis on membrane microparticles found in human plasma. Transfusion 2002;42:334-342.
197.
Hwang HS, Park SH, Park YW, Kwon HS, Sohn IS: Expression of cellular prion protein in the placentas of women with normal and preeclamptic pregnancies. Acta Obstet Gynecol Scand 2010;89:1155-1161.
198.
Caniggia I, Winter J, Lye SJ, Post M: Oxygen and placental development during the first trimester: implications for the pathophysiology of pre-eclampsia. Placenta 2000;21 (suppl A):S25-S30.
199.
Jeong JK, Seo JS, Moon MH, Lee YJ, Seol JW, Park SY: Hypoxia-inducible factor-1 α regulates prion protein expression to protect against neuron cell damage. Neurobiol Aging 2012;33:1006.e1-e10.
200.
Liang J, Bai F, Luo G, Wang J, Liu J, Ge F, Pan Y, Yao L, Du R, Li X, Fan R, Zhang H, Guo X, Wu K, Fan D: Hypoxia induced overexpression of PrP(C) in gastric cancer cell lines. Cancer Biol Ther 2007;6:769-774.
201.
Seo JS, Seol JW, Moon MH, Jeong JK, Lee YJ, Park SY: Hypoxia protects neuronal cells from human prion protein fragment-induced apoptosis. J Neurochem 2010;112:715-722.
202.
Jeong JK, Park SY: Transcriptional regulation of specific protein 1 (SP1) by hypoxia-inducible factor 1 alpha (HIF-1α) leads to PRNP expression and neuroprotection from toxic prion peptide. Biochem Biophys Res Commun 2012;429:93-98.
203.
Mitsios N, Saka M, Krupinski J, Pennucci R, Sanfeliu C, Miguel Turu M, Gaffney J, Kumar P, Kumar S, Sullivan M, Slevin M: Cellular prion protein is increased in the plasma and peri-infarcted brain tissue after acute stroke. J Neurosci Res 2007;85:602-611.
204.
Shyu WC, Lin SZ, Chiang MF, Ding DC, Li KW, Chen SF, Yang HI, Li H: Overexpression of PrPC by adenovirus-mediated gene targeting reduces ischemic injury in a stroke rat model. J Neurosci 2005;25:8967-8977.
205.
Weise J, Crome O, Sandau R, Schulz-Schaeffer W, Bähr M, Zerr I: Upregulation of cellular prion protein (PrPc) after focal cerebral ischemia and influence of lesion severity. Neurosci Lett 2004;372:146-150.
206.
Watanabe T, Yasutaka Y, Nishioku T, Kusakabe S, Futagami K, Yamauchi A, Kataoka Y: Involvement of the cellular prion protein in the migration of brain microvascular endothelial cells. Neurosci Lett 2011;496:121-124.
207.
Krupinski J, Turu MM, Luque A, Badimon L, Slevin M: Increased PrPC expression correlates with endoglin (CD105) positive microvessels in advanced carotid lesions. Acta Neuropathol 2008;116:537-545.
208.
Starke R, Drummond O, MacGregor I, Biggerstaff J, Gale R, Camilleri R, Mackie I, Machin S, Harrison P: The expression of prion protein by endothelial cells: a source of the plasma form of prion protein? Br J Haematol 2002;119:863-873.
209.
Viegas P, Chaverot N, Enslen H, Perrière N, Couraud PO, Cazaubon S: Junctional expression of the prion protein PrPC by brain endothelial cells: a role in trans-endothelial migration of human monocytes. J Cell Sci 2006;119(Pt 22):4634-4643.
210.
Lemaire-Vieille C, Schulze T, Podevin-Dimster V, Follet J, Bailly Y, Blanquet-Grossard F, Decavel JP, Heinen E, Cesbron JY: Epithelial and endothelial expression of the green fluorescent protein reporter gene under the control of bovine prion protein (PrP) gene regulatory sequences in transgenic mice. Proc Natl Acad Sci USA 2000;97:5422-5427.
211.
Sivakumaran M: The expression of prion protein (PrPc) by endothelial cells: an in vitro culture-induced artefactual phenomenon? Br J Haematol 2003;121:673-674.
212.
Bush CJ, Szasz T, Johnson KB, Tykocki NR, Surewicz WK, Watson RE, Watts SW: Expression and potential function of prion protein in the vasculature. Reinvention 2011;4.
213.
Satoh J, Kuroda Y, Katamine S: Gene expression profile in prion protein-deficient fibroblasts in culture. Am J Pathol 2000;157:59-68.
214.
Zocche Soprana H, Canes Souza L, Debbas V, Martins Laurindo FR: Cellular prion protein (PrP(C)) and superoxide dismutase (SOD) in vascular cells under oxidative stress. Exp Toxicol Pathol 2011;63:229-236.
215.
Aikawa T, Whipple CA, Lopez ME, Gunn J, Young A, Lander AD, Korc M: Glypican-1 modulates the angiogenic and metastatic potential of human and mouse cancer cells. J Clin Invest 2008;118:89-99.
216.
Cheng F, Lindqvist J, Haigh CL, Brown DR, Mani K: Copper-dependent co-internalization of the prion protein and glypican-1. J Neurochem 2006;98:1445-1457.
217.
Mani K, Cheng F, Havsmark B, Jönsson M, Belting M, Fransson LA: Prion, amyloid beta-derived Cu(II) ions, or free Zn(II) ions support S-nitroso-dependent autocleavage of glypican-1 heparan sulfate. J Biol Chem 2003;278:38956-38965.
218.
Qiao D, Meyer K, Mundhenke C, Drew SA, Friedl A: Heparan sulfate proteoglycans as regulators of fibroblast growth factor-2 signaling in brain endothelial cells. Specific role for glypican-1 in glioma angiogenesis. J Biol Chem 2003;278:16045-16053.
219.
Gengrinovitch S, Berman B, David G, Witte L, Neufeld G, Ron D: Glypican-1 is a VEGF165 binding proteoglycan that acts as an extracellular chaperone for VEGF165. J Biol Chem 1999;274:10816-10822.
220.
Belting M, Mani K, Jönsson M, Cheng F, Sandgren S, Jonsson S, Ding K, Delcros JG, Fransson LA: Glypican-1 is a vehicle for polyamine uptake in mammalian cells: a pivotal role for nitrosothiol-derived nitric oxide. J Biol Chem 2003;278:47181-47189.
221.
Ding K, Mani K, Cheng F, Belting M, Fransson LA: Copper-dependent autocleavage of glypican-1 heparan sulfate by nitric oxide derived from intrinsic nitrosothiols. J Biol Chem 2002;277:33353-33360.
222.
Mani K, Cheng F, Havsmark B, David S, Fransson LA: Involvement of glycosylphosphatidylinositol-linked ceruloplasmin in the copper/zinc-nitric oxide-dependent degradation of glypican-1 heparan sulfate in rat C6 glioma cells. J Biol Chem 2004;279:12918-12923.
223.
Cappai R, Cheng F, Ciccotosto GD, Needham BE, Masters CL, Multhaup G, Fransson LA, Mani K: The amyloid precursor protein (APP) of Alzheimer disease and its paralog, APLP2, modulate the Cu/Zn-nitric oxide-catalyzed degradation of glypican-1 heparan sulfate in vivo. J Biol Chem 2005;280:13913-13920.
224.
Yoshida D, Ikeda Y, Nakazawa S: Quantitative analysis of copper, zinc and copper/zinc ratio in selected human brain tumors. J Neurooncol 1993;16:109-115.
225.
Gupta SK, Shukla VK, Vaidya MP, Roy SK, Gupta S: Serum trace elements and Cu/Zn ratio in breast cancer patients. J Surg Oncol 1991;46:178-181.
226.
Cunzhi H, Jiexian J, Xianwen Z, Jingang G, Shumin Z, Lili D: Serum and tissue levels of six trace elements and copper/zinc ratio in patients with cervical cancer and uterine myoma. Biol Trace Elem Res 2003;94:113-122.
227.
Gupta SK, Shukla VK, Vaidya MP, Roy SK, Gupta S: Serum and tissue trace elements in colorectal cancer. J Surg Oncol 1993;52:172-175.
228.
Poo JL, Rosas-Romero R, Montemayor AC, Isoard F, Uribe M: Diagnostic value of the copper/zinc ratio in hepatocellular carcinoma: a case control study. J Gastroenterol 2003;38:45-51.
229.
Safi R, Nelson ER, Chitneni SK, Franz KJ, George DJ, Zalutsky MR, McDonnell DP: Copper signaling axis as a target for prostate cancer therapeutics. Cancer Res 2014;74:5819-5831.
230.
Nayak SB, Bhat VR, Upadhyay D, Udupa SL: Copper and ceruloplasmin status in serum of prostate and colon cancer patients. Indian J Physiol Pharmacol 2003;47:108-110.
231.
Upadhya S, Upadhya S, Prabhu KS: Serum glycoconjugates and ceruloplasmin in cancer of uterine cervix. Indian J Clin Biochem 2002;17:202-204.
232.
Vaidya SM, Kamalakar PL: Copper and ceruloplasmin levels in serum of women with breast cancer. Indian J Med Sci 1998;52:184-187.
233.
Geetha A, Saranya P, Annie Jeyachristy S, Surendran R, Sundaram A: Relevance of non-ceruloplasmin copper to oxidative stress in patients with hepatocellular carcinoma. Biol Trace Elem Res 2009;130:229-240.
234.
Senra Varela A, Lopez Saez JJ, Quintela Senra D: Serum ceruloplasmin as a diagnostic marker of cancer. Cancer Lett 1997;121:139-145.
235.
Crowe A, Jackaman C, Beddoes KM, Ricciardo B, Nelson DJ: Rapid copper acquisition by developing murine mesothelioma: decreasing bioavailable copper slows tumor growth, normalizes vessels and promotes T cell infiltration. PLoS One 2013;8:e73684.
236.
Auerbach R, Alby L, Morrissey LW, Tu M, Joseph J: Expression of organ-specific antigens on capillary endothelial cells. Microvasc Res 1985;29:401-411.
237.
Brem SS, Zagzag D, Tsanaclis AM, Gately S, Elkouby MP, Brien SE: Inhibition of angiogenesis and tumor growth in the brain. Suppression of endothelial cell turnover by penicillamine and the depletion of copper, an angiogenic cofactor. Am J Pathol 1990;137:1121-1142.
238.
Yoshida D, Ikeda Y, Nakazawa S: Copper chelation inhibits tumor angiogenesis in the experimental 9L gliosarcoma model. Neurosurgery 1995;37:287-292.
239.
Pan Q, Kleer CG, van Golen KL, Irani J, Bottema KM, Bias C, De Carvalho M, Mesri EA, Robins DM, Dick RD, Brewer GJ, Merajver SD: Copper deficiency induced by tetrathiomolybdate suppresses tumor growth and angiogenesis. Cancer Res 2002;62:4854-4859.
240.
Jain S, Cohen J, Ward MM, Kornhauser N, Chuang E, Cigler T, Moore A, Donovan D, Lam C, Cobham MV, Schneider S, Hurtado Rúa SM, Benkert S, Mathijsen Greenwood C, Zelkowitz R, Warren JD, Lane ME, Mittal V, Rafii S, Vahdat LT: Tetrathiomolybdate-associated copper depletion decreases circulating endothelial progenitor cells in women with breast cancer at high risk of relapse. Ann Oncol 2013;24:1491-1498.
241.
Brem S, Grossman SA, Carson KA, New P, Phuphanich S, Alavi JB, Mikkelsen T, Fisher JD: New Approaches to Brain Tumor Therapy CNS Consortium. Phase 2 trial of copper depletion and penicillamine as antiangiogenesis therapy of glioblastoma. Neuro Oncol 2005;7:246-253.
242.
Redman BG, Esper P, Pan Q, Dunn RL, Hussain HK, Chenevert T, Brewer GJ, Merajver SD: Phase II trial of tetrathiomolybdate in patients with advanced kidney cancer. Clin Cancer Res 2003;9:1666-1672.
243.
Brewer GJ, Dick RD, Grover DK, LeClaire V, Tseng M, Wicha M, Pienta K, Redman BG, Jahan T, Sondak VK, Strawderman M, LeCarpentier G, Merajver SD: Treatment of metastatic cancer with tetrathiomolybdate, an anticopper, antiangiogenic agent: phase I study. Clin Cancer Res 2000;6:1-10.
244.
Alvarez HM, Xue Y, Robinson CD, Canalizo-Hernández MA, Marvin RG, Kelly RA, Mondragón A, Penner-Hahn JE, O'Halloran TV: Tetrathiomolybdate inhibits copper trafficking proteins through metal cluster formation. Science 2010;327:331-334.
245.
Brewer GJ: Tetrathiomolybdate anticopper therapy for Wilson's disease inhibits angiogenesis, fibrosis and inflammation. J Cell Mol Med 2003;7:11-20.
246.
Lowndes SA, Sheldon HV, Cai S, Taylor JM, Harris AL: Copper chelator ATN-224 inhibits endothelial function by multiple mechanisms. Microvasc Res 2009;77:314-326.
247.
Juarez JC, Betancourt O Jr, Pirie-Shepherd SR, Guan X, Price ML, Shaw DE, Mazar AP, Doñate F: Copper binding by tetrathiomolybdate attenuates angiogenesis and tumor cell proliferation through the inhibition of superoxide dismutase 1. Clin Cancer Res 2006;12:4974-4982.
248.
Juarez JC, Manuia M, Burnett ME, Betancourt O, Boivin B, Shaw DE, Tonks NK, Mazar AP, Doñate F: Superoxide dismutase 1 (SOD1) is essential for H2O2-mediated oxidation and inactivation of phosphatases in growth factor signaling. Proc Natl Acad Sci USA 2008;105:7147-7152.
249.
Moriguchi M, Nakajima T, Kimura H, Watanabe T, Takashima H, Mitsumoto Y, Katagishi T, Okanoue T, Kagawa K: The copper chelator trientine has an antiangiogenic effect against hepatocellular carcinoma, possibly through inhibition of interleukin-8 production. Int J Cancer 2002;102:445-452.
250.
Rofstad EK, Halsor EF: Vascular endothelial growth factor, interleukin-8, platelet-derived endothelial cell growth factor, and basic fibroblast growth factor promote angiogenesis and metastasis in human melanoma xenografts. Cancer Res 2000;60:4932-4938.
251.
Perera VS, Wu H, Yang LD, Huang SD, Fraizer GC: Inhibition of vascular endothelial cell tube formation by zinc nanoparticles. Cancer Res 2013;73(suppl 1):A1615.
252.
Menen RS, Hassanein MK, Momiyama M, Suetsugu A, Moossa AR, Hoffman RM, Bouvet M: Tumor-educated macrophages promote tumor growth and peritoneal metastasis in an orthotopic nude mouse model of human pancreatic cancer. In Vivo 2012;26:565-569.
253.
Joimel U, Gest C, Soria J, Pritchard LL, Alexandre J, Laurent M, Blot E, Cazin L, Vannier JP, Varin R, Li H, Soria C: Stimulation of angiogenesis resulting from cooperation between macrophages and MDA-MB-231 breast cancer cells: proposed molecular mechanism and effect of tetrathiomolybdate. BMC Cancer 2010;10:375.
254.
Stadler N, Lindner RA, Davies MJ: Direct detection and quantification of transition metal ions in human atherosclerotic plaques: evidence for the presence of elevated levels of iron and copper. Arterioscler Thromb Vasc Biol 2004;24:949-954.
255.
Iskra M, Patelski J, Majewski W: Relationship of calcium, magnesium, zinc and copper concentrations in the arterial wall and serum in atherosclerosis obliterans and aneurysm. J Trace Elem Med Biol 1997;11:248-252.
256.
Itoh S, Kim HW, Nakagawa O, Ozumi K, Lessner SM, Aoki H, Akram K, McKinney RD, Ushio-Fukai M, Fukai T: Novel role of antioxidant-1 (Atox1) as a copper-dependent transcription factor involved in cell proliferation. J Biol Chem 2008;283:9157-9167.
257.
Iskra M, Majewski W: Copper and zinc concentrations and the activities of ceruloplasmin and superoxide dismutase in atherosclerosis obliterans. Biol Trace Elem Res 2000;73:55-65.
258.
Bar-Or D, Thomas GW, Yukl RL, Rael LT, Shimonkevitz RP, Curtis CG, Winkler JV: Copper stimulates the synthesis and release of interleukin-8 in human endothelial cells: a possible early role in systemic inflammatory responses. Shock 2003;20:154-158.
259.
Wei H, Zhang WJ, Leboeuf R, Frei B: Copper induces - and copper chelation by tetrathiomolybdate inhibits - endothelial activation in vitro. Redox Rep 2014;19:40-48.
260.
Trickler WJ, Lantz SM, Schrand AM, Robinson BL, Newport GD, Schlager JJ, Paule MG, Slikker W, Biris AS, Hussain SM, Ali SF: Effects of copper nanoparticles on rat cerebral microvessel endothelial cells. Nanomedicine (Lond) 2012;7:835-846.
261.
Trickler WJ, Lantz-McPeak SM, Robinson BL, Paule MG, Slikker W Jr, Biris AS, Schlager JJ, Hussain SM, Kanungo J, Gonzalez C, Ali SF: Porcine brain microvessel endothelial cells show pro-inflammatory response to the size and composition of metallic nanoparticles. Drug Metab Rev 2014;46:224-231.
262.
Mandinov L, Mandinova A, Kyurkchiev S, Kyurkchiev D, Kehayov I, Kolev V, Soldi R, Bagala C, de Muinck ED, Lindner V, Post MJ, Simons M, Bellum S, Prudovsky I, Maciag T: Copper chelation represses the vascular response to injury. Proc Natl Acad Sci USA 2003;100:6700-6705.
263.
Schuschke DA, Percival SS, Lominadze D, Saari JT, Lentsch AB: Tissue-specific ICAM-1 expression and neutrophil transmigration in the copper-deficient rat. Inflammation 2002;26:297-303.
264.
Lominadze D, Saari JT, Percival SS, Schuschke DA: Proinflammatory effects of copper deficiency on neutrophils and lung endothelial cells. Immunol Cell Biol 2004;82:231-238.
265.
Clark PR, Manes TD, Pober JS, Kluger MS: Increased ICAM-1 expression causes endothelial cell leakiness, cytoskeletal reorganization and junctional alterations. J Invest Dermatol 2007;127:762-774.
266.
Gordon SA, Lominadze D, Saari JT, Lentsch AB, Schuschke DA: Impaired deformability of copper-deficient neutrophils. Exp Biol Med 2005;230:543-548.
267.
Karimbakas J, Langkamp-Henken B, Percival SS: Arrested maturation of granulocytes in copper deficient mice. J Nutr 1998;128:1855-1860.
268.
Bogaard HJ, Mizuno S, Guignabert C, Al Hussaini AA, Farkas D, Ruiter G, Kraskauskas D, Fadel E, Allegood JC, Humbert M, Vonk Noordegraaf A, Spiegel S, Farkas L, Voelkel NF: Copper dependence of angioproliferation in pulmonary arterial hypertension in rats and humans. Am J Respir Cell Mol Biol 2012;46:582-591.
269.
Wei H, Frei B, Beckman JS, Zhang WJ: Copper chelation by tetrathiomolybdate inhibits lipopolysaccharide-induced inflammatory responses in vivo. Am J Physiol Heart Circ Physiol 2011;301:H712-H720.
270.
Wei H, Zhang WJ, McMillen TS, Leboeuf RC, Frei B: Copper chelation by tetrathiomolybdate inhibits vascular inflammation and atherosclerotic lesion development in apolipoprotein E-deficient mice. Atherosclerosis 2012;223:306-313.
271.
Madarić A, Ginter E, Kadrabová J: Serum copper, zinc and copper/zinc ratio in males: influence of aging. Physiol Res 1994;43:107-111.
272.
Wang JC, Bennett M: Aging and atherosclerosis: mechanisms, functional consequences, and potential therapeutics for cellular senescence. Circ Res 2012;111:245-259.
273.
Xu D, Neville R, Finkel T: Homocysteine accelerates endothelial cell senescence. FEBS Lett 2000;470:20-24.
274.
Starkebaum G, Harlan JM: Endothelial cell injury due to copper-catalyzed hydrogen peroxide generation from homocysteine. J Clin Invest 1986;77:1370-1376.
275.
Boilan E, Winant V, Dumortier E, Piret JP, Bonfitto F, Osiewacz HD, Debacq-Chainiaux F, Toussaint O: Role of p38MAPK and oxidative stress in copper-induced senescence. Age (Dordr) 2013;35:2255-2271.
276.
Matos L, Gouveia A, Almeida H: Copper ability to induce premature senescence in human fibroblasts. Age (Dordr) 2012;34:783-794.
277.
Newman AC, Nakatsu MN, Chou W, Gershon PD, Hughes CC: The requirement for fibroblasts in angiogenesis: fibroblast-derived matrix proteins are essential for endothelial cell lumen formation. Mol Biol Cell 2011;22:3791-3800.
278.
Ferns GA, Lamb DJ, Taylor A: The possible role of copper ions in atherogenesis: the Blue Janus. Atherosclerosis 1997;133:139-152.
279.
Jaba IM, Zhuang ZW, Li N, Jiang Y, Martin KA, Sinusas AJ, Papademetris X, Simons M, Sessa WC, Young LH, Tirziu D: NO triggers RGS4 degradation to coordinate angiogenesis and cardiomyocyte growth. J Clin Invest 2013;123:1718-1731.
280.
Sutendra G, Dromparis P, Paulin R, Zervopoulos S, Haromy A, Nagendran J, Michelakis ED: A metabolic remodeling in right ventricular hypertrophy is associated with decreased angiogenesis and a transition from a compensated to a decompensated state in pulmonary hypertension. J Mol Med (Berl) 2013;91:1315-1327.
281.
Hou J, Kang YJ: Regression of pathological cardiac hypertrophy: signalling pathways and therapeutic targets. Pharmacol Ther 2012;135:337-354.
282.
Klevay LM: Cardiovascular disease from copper deficiency - a history. J Nutr 2000;130(2S Suppl):489S-492S.
283.
Chevion M, Jiang Y, Har-El R, Berenshtein E, Uretzky G, Kitrossky N: Copper and iron are mobilized following myocardial ischemia: possible predictive criteria for tissue injury. Proc Natl Acad Sci USA 1993;90:1102-1106.
284.
Berenshtein E, Mayer B, Goldberg C, Kitrossky N, Chevion M: Patterns of mobilization of copper and iron following myocardial ischemia: possible predictive criteria for tissue injury. J Mol Cell Cardiol 1997;29:3025-3034.
285.
Shokrzadeh M, Ghaemian A, Salehifar E, Aliakbari S, Saravi SS, Ebrahimi P: Serum zinc and copper levels in ischemic cardiomyopathy. Biol Trace Elem Res 2009;127:116-123.
286.
Zhou Y, Jiang Y, Kang YJ: Copper reverses cardiomyocyte hypertrophy through vascular endothelial growth factor-mediated reduction in the cell size. J Mol Cell Cardiol 2008;45:106-117.
287.
Getz J, Lin D, Medeiros DM: The cardiac copper chaperone proteins Sco1 and CCS are up-regulated, but Cox 1 and Cox4 are down-regulated, by copper deficiency. Biol Trace Elem Res 2011;143:368-377.
288.
Zuo X, Xie H, Dong D, Jiang N, Zhu H, Kang YJ: Cytochrome c oxidase is essential for copper-induced regression of cardiomyocyte hypertrophy. Cardiovasc Toxicol 2010;10:208-215.
289.
Zhang YE, Wang JN, Tang JM, Guo LY, Yang JY, Huang YZ, Tan Y, Fu SZ, Kong X, Zheng F: In vivo protein transduction: delivery of PEP-1-SOD1 fusion protein into myocardium efficiently protects against ischemic insult. Mol Cells 2009;27:159-166.
290.
Wang JN, Ding P, Huang YZ, Luo LN, Guo LY, Kong X, Shao F: The protective effect of PEP-1-SOD1 preconditioning on hypoxia/reoxygenation injury in cultured human umbilical vein endothelial cells. Zhonghua Xin Xue Guan Bing Za Zhi 2007;35:750-756.
291.
Hughes WM Jr, Rodriguez WE, Rosenberger D, Chen J, Sen U, Tyagi N, Moshal KS, Vacek T, Kang YJ, Tyagi SC: Role of copper and homocysteine in pressure overload heart failure. Cardiovasc Toxicol 2008;8:137-144.
292.
Kang YJ: Copper and homocysteine in cardiovascular diseases. Pharmacol Ther 2011;129:321-331.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.