title: Copper Transport Protein Antioxidant-1 Promotes Inflammatory Neovascularization via Chaperone and Transcription Factor Function.
abstract: Copper (Cu), an essential micronutrient, plays a fundamental role in inflammation and angiogenesis; however, its precise mechanism remains undefined. Here we uncover a novel role of Cu transport protein Antioxidant-1 (Atox1), which is originally appreciated as a Cu chaperone and recently discovered as a Cu-dependent transcription factor, in inflammatory neovascularization. Atox1 expression is upregulated in patients and mice with critical limb ischemia. Atox1-deficient mice show impaired limb perfusion recovery with reduced arteriogenesis, angiogenesis, and recruitment of inflammatory cells. In vivo intravital microscopy, bone marrow reconstitution, and Atox1 gene transfer in Atox1(-/-) mice show that Atox1 in endothelial cells (ECs) is essential for neovascularization and recruitment of inflammatory cells which release VEGF and TNFα. Mechanistically, Atox1-depleted ECs demonstrate that Cu chaperone function of Atox1 mediated through Cu transporter ATP7A is required for VEGF-induced angiogenesis via activation of Cu enzyme lysyl oxidase. Moreover, Atox1 functions as a Cu-dependent transcription factor for NADPH oxidase organizer p47phox, thereby increasing ROS-NFκB-VCAM-1/ICAM-1 expression and monocyte adhesion in ECs inflamed with TNFα in an ATP7A-independent manner. These findings demonstrate a novel linkage between Atox1 and NADPH oxidase involved in inflammatory neovascularization and suggest Atox1 as a potential therapeutic target for treatment of ischemic disease.
authors.affiliation: Departments of Medicine (Section of Cardiology) and Pharmacology, University of Illinois at Chicago, Chicago, IL.
authors.forename: Gin-Fu
authors.initials: GF
authors.lastname: Chen
authors.affiliation: Departments of Medicine (Section of Cardiology) and Pharmacology, University of Illinois at Chicago, Chicago, IL.|Center for Cardiovascular Research, University of Illinois at Chicago, Chicago, IL.|Jesse Brown Veterans Affairs Medical Center, Chicago, IL.
authors.forename: Varadarajan
authors.initials: V
authors.lastname: Sudhahar
authors.affiliation: Department of Pharmacology, University of Illinois at Chicago, Chicago, IL.|Center for Cardiovascular Research, University of Illinois at Chicago, Chicago, IL.
authors.forename: Seock-Won
authors.initials: SW
authors.lastname: Youn
authors.affiliation: Departments of Medicine (Section of Cardiology) and Pharmacology, University of Illinois at Chicago, Chicago, IL.|Center for Cardiovascular Research, University of Illinois at Chicago, Chicago, IL.
authors.forename: Archita
authors.initials: A
authors.lastname: Das
authors.affiliation: Department of Pharmacology, University of Illinois at Chicago, Chicago, IL.
authors.forename: Jaehyung
authors.initials: J
authors.lastname: Cho
authors.affiliation: Departments of Medicine (Section of Cardiology) and Pharmacology, University of Illinois at Chicago, Chicago, IL.|Center for Cardiovascular Research, University of Illinois at Chicago, Chicago, IL.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Kamiya
authors.affiliation: Department of Pharmacology, University of Illinois at Chicago, Chicago, IL.
authors.forename: Norifumi
authors.initials: N
authors.lastname: Urao
authors.affiliation: Departments of Medicine (Section of Cardiology) and Pharmacology, University of Illinois at Chicago, Chicago, IL.|Department of Pharmacology, University of Illinois at Chicago, Chicago, IL.|Jesse Brown Veterans Affairs Medical Center, Chicago, IL.
authors.forename: Ronald D
authors.initials: RD
authors.lastname: McKinney
authors.affiliation: Departments of Medicine (Section of Cardiology) and Pharmacology, University of Illinois at Chicago, Chicago, IL.
authors.forename: Bayasgalan
authors.initials: B
authors.lastname: Surenkhuu
authors.affiliation: Department of Quantitative Biology and Medicine, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Hamakubo
authors.affiliation: Department of Quantitative Biology and Medicine, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Iwanari
authors.affiliation: Department of Medicine, University of Texas Health Science Center, San Antonio, Texas.
authors.forename: Senlin
authors.initials: S
authors.lastname: Li
authors.affiliation: Division of Pulmonary, Allergy, Critical Care and Sleep Medicine The Ohio State University Wexner Medical Center, OH.
authors.forename: John W
authors.initials: JW
authors.lastname: Christman
authors.affiliation: Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol.
authors.forename: Saran
authors.initials: S
authors.lastname: Shantikumar
authors.affiliation: Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol.|National Heart and Lung Institute, Imperial College of London, London, UK.
authors.forename: Gianni D
authors.initials: GD
authors.lastname: Angelini
authors.affiliation: Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol.|National Heart and Lung Institute, Imperial College of London, London, UK.
authors.forename: Costanza
authors.initials: C
authors.lastname: Emanueli
authors.affiliation: Department of Pharmacology, University of Illinois at Chicago, Chicago, IL.|Center for Cardiovascular Research, University of Illinois at Chicago, Chicago, IL.
authors.forename: Masuko
authors.initials: M
authors.lastname: Ushio-Fukai
authors.affiliation: Departments of Medicine (Section of Cardiology) and Pharmacology, University of Illinois at Chicago, Chicago, IL.|Department of Pharmacology, University of Illinois at Chicago, Chicago, IL.|Center for Cardiovascular Research, University of Illinois at Chicago, Chicago, IL.|Jesse Brown Veterans Affairs Medical Center, Chicago, IL.
authors.forename: Tohru
authors.initials: T
authors.lastname: Fukai
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D027682:Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D000079922:Copper Transport Proteins; D000073840:Copper-Transporting ATPases; D005786:Gene Expression Regulation; D006614:Hindlimb; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007511:Ischemia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007866:Leg / Q000098:blood supply / Q000473:pathology; D056511:Metallochaperones / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018832:Molecular Chaperones; D009000:Monocytes / Q000378:metabolism / Q000473:pathology; D019255:NADPH Oxidases / Q000235:genetics* / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008249:Protein-Lysine 6-Oxidase / Q000235:genetics* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: C474500:ATOX1 protein, human; D027682:Cation Transport Proteins; D015815:Cell Adhesion Molecules; D000079922:Copper Transport Proteins; D056511:Metallochaperones; D018832:Molecular Chaperones; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D008249:Protein-Lysine 6-Oxidase; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D000251:Adenosine Triphosphatases; C081184:ATP7A protein, human; D000073840:Copper-Transporting ATPases