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Copper transport protein antioxidant-1 promotes inflammatory neovascularization via chaperone and transcription factor function
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Chen, Gin-Fu, Sudhahar, Varadarajan, Youn, Seock-Won, Das, Archita, Cho, Jaehyung, Kamiya, Tetsuro, Urao, Norifumi, McKinney, Ronald D., Surenkhuu, Bayasgalan, Hamakubo, Takao, Iwanari, Hiroko, Li, Senlin, Christman, John W., Shantikumar, Saran, Angelini, Gianni D., Emanueli, Costanza, Ushio-Fukai, Masuko and Fukai, Tohru (2015) Copper transport protein antioxidant-1 promotes inflammatory neovascularization via chaperone and transcription factor function. Scientific Reports, 5 . 14780. doi:10.1038/srep14780
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Official URL: http://dx.doi.org/10.1038/srep14780
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.
| Item Type: | Journal Article | ||||||
|---|---|---|---|---|---|---|---|
| Divisions: | Faculty of Medicine > Warwick Medical School | ||||||
| Journal or Publication Title: | Scientific Reports | ||||||
| Publisher: | Nature Publishing Group | ||||||
| ISSN: | 2045-2322 | ||||||
| Official Date: | 6 September 2015 | ||||||
| Dates: |
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| Volume: | 5 | ||||||
| Article Number: | 14780 | ||||||
| DOI: | 10.1038/srep14780 | ||||||
| Status: | Peer Reviewed | ||||||
| Publication Status: | Published | ||||||
| Access rights to Published version: | Open Access |
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