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Sci Rep. 2015 Oct 6;5:14780. doi: 10.1038/srep14780.

Copper Transport Protein Antioxidant-1 Promotes Inflammatory Neovascularization via Chaperone and Transcription Factor Function.

Author information

1
Departments of Medicine (Section of Cardiology) and Pharmacology, University of Illinois at Chicago, Chicago, IL.
2
Center for Cardiovascular Research, University of Illinois at Chicago, Chicago, IL.
3
Jesse Brown Veterans Affairs Medical Center, Chicago, IL.
4
Department of Pharmacology, University of Illinois at Chicago, Chicago, IL.
5
Department of Quantitative Biology and Medicine, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo, Japan.
6
Department of Medicine, University of Texas Health Science Center, San Antonio, Texas.
7
Division of Pulmonary, Allergy, Critical Care and Sleep Medicine The Ohio State University Wexner Medical Center, OH.
8
Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol.
9
National Heart and Lung Institute, Imperial College of London, London, UK.

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.

PMID:
26437801
PMCID:
PMC4594038
DOI:
10.1038/srep14780
[Indexed for MEDLINE]
Free PMC Article

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