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

• Published in: Scientific reports 2015-10, Vol.5 (1), p.14780-14780, Article 14780
• Main Authors: 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, Fukai, Tohru
• Format: Article
• Language: English
• Subjects: 13/89; 13/95; 38/5; 631/80/304; 64/60; 692/4019/592; 82/1; 82/51; 96/1; 96/106; 96/109; 96/95; Adenosine Triphosphatases - genetics; Adenosine Triphosphatases - metabolism; Angiogenesis; Animals; Antioxidants; Atox1 gene; Bone marrow; Cation Transport Proteins - genetics; Cation Transport Proteins - metabolism; Cell Adhesion Molecules - genetics; Cell Adhesion Molecules - metabolism; Cell Line; Copper; Copper Transport Proteins; Copper-Transporting ATPases; Endothelial cells; Gene Expression Regulation; Gene transfer; Genes; Hindlimb; Human Umbilical Vein Endothelial Cells - cytology; Human Umbilical Vein Endothelial Cells - metabolism; Humanities and Social Sciences; Humans; Inflammation; Intercellular adhesion molecule 1; Ischemia; Ischemia - genetics; Ischemia - metabolism; Ischemia - pathology; Leg - blood supply; Leg - pathology; Lysyl oxidase; Metallochaperones - genetics; Metallochaperones - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Chaperones; Monocytes; Monocytes - metabolism; Monocytes - pathology; multidisciplinary; NAD(P)H oxidase; NADPH Oxidases - genetics; NADPH Oxidases - metabolism; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - metabolism; Neovascularization, Pathologic - pathology; NF-κB protein; Perfusion; Protein transport; Protein-Lysine 6-Oxidase - genetics; Protein-Lysine 6-Oxidase - metabolism; Reactive oxygen species; Reactive Oxygen Species - metabolism; Rodents; Science; Signal Transduction; Transcription factors; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism; Vascular cell adhesion molecule 1; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism; Vascularization
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep14780

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.