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

Gin Fu Chen, Sudhahar Varadarajan, Seock Won Youn, Archita Das, Jaehyung Cho, Tetsuro Kamiya, Norifumi Urao, Ronald D. McKinney, Bayasgalan Surenkhuu, Takao Hamakubo, Hiroko Iwanari, Senlin Li, John W. Christman, Saran Shantikumar, Gianni D. Angelini, Costanza Emanueli, Masuko Fukai, Tohru Fukai

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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-NFΰ B-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.

Original languageEnglish (US)
Article number14780
JournalScientific reports
Volume5
DOIs
StatePublished - Oct 6 2015

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    Chen, G. F., Varadarajan, S., Youn, S. W., Das, A., Cho, J., Kamiya, T., Urao, N., McKinney, R. D., Surenkhuu, B., Hamakubo, T., Iwanari, H., Li, S., Christman, J. W., Shantikumar, S., Angelini, G. D., Emanueli, C., Fukai, M., & Fukai, T. (2015). Copper Transport Protein Antioxidant-1 Promotes Inflammatory Neovascularization via Chaperone and Transcription Factor Function. Scientific reports, 5, [14780]. https://doi.org/10.1038/srep14780