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

Gin-Fu Chen, Varadarajan Sudhahar, 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 Ushio-Fukai, Tohru Fukai

Research output: Contribution to journalArticle (Academic Journal)peer-review

36 Citations (Scopus)
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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-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.

Original languageEnglish
Article number14780
Number of pages20
JournalScientific Reports
Volume5
DOIs
Publication statusPublished - 6 Oct 2015

Structured keywords

  • Centre for Surgical Research

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