Journal Article

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

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

2015

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 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