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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.

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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.
Department of Pharmacology, University of Illinois at Chicago, Chicago, IL.
Department of Quantitative Biology and Medicine, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo, Japan.
Department of Medicine, University of Texas Health Science Center, San Antonio, Texas.
Division of Pulmonary, Allergy, Critical Care and Sleep Medicine The Ohio State University Wexner Medical Center, OH.
Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol.
National Heart and Lung Institute, Imperial College of London, London, UK.


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.

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