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

Research output: Contribution to journalArticle

23 Citations (Scopus)

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

Fingerprint

Copper
Carrier Proteins
Transcription Factors
Antioxidants
Endothelial Cells
Vascular Endothelial Growth Factor A
Extremities
Protein-Lysine 6-Oxidase
Enzyme Activation
Vascular Cell Adhesion Molecule-1
NADPH Oxidase
Micronutrients
Intercellular Adhesion Molecule-1
Monocytes
Ischemia
Perfusion
Bone Marrow
Inflammation
Therapeutics

ASJC Scopus subject areas

  • General

Cite this

Copper Transport Protein Antioxidant-1 Promotes Inflammatory Neovascularization via Chaperone and Transcription Factor Function. / Chen, Gin Fu; Varadarajan, Sudhahar; 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; Fukai, Masuko; Fukai, Tohru.

In: Scientific Reports, Vol. 5, 14780, 06.10.2015.

Research output: Contribution to journalArticle

Chen, GF, Varadarajan, S, Youn, SW, Das, A, Cho, J, Kamiya, T, Urao, N, McKinney, RD, Surenkhuu, B, Hamakubo, T, Iwanari, H, Li, S, Christman, JW, Shantikumar, S, Angelini, GD, Emanueli, C, Fukai, M & Fukai, T 2015, 'Copper Transport Protein Antioxidant-1 Promotes Inflammatory Neovascularization via Chaperone and Transcription Factor Function', Scientific Reports, vol. 5, 14780. https://doi.org/10.1038/srep14780
Chen, Gin Fu ; Varadarajan, Sudhahar ; 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 ; Fukai, Masuko ; Fukai, Tohru. / Copper Transport Protein Antioxidant-1 Promotes Inflammatory Neovascularization via Chaperone and Transcription Factor Function. In: Scientific Reports. 2015 ; Vol. 5.
@article{a169a1064136474eb7f0b8031adb88a8,
title = "Copper Transport Protein Antioxidant-1 Promotes Inflammatory Neovascularization via Chaperone and Transcription Factor Function",
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-NF{\^I}° 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.",
author = "Chen, {Gin Fu} and Sudhahar Varadarajan and Youn, {Seock Won} and Archita Das and Jaehyung Cho and Tetsuro Kamiya and Norifumi Urao and McKinney, {Ronald D.} and Bayasgalan Surenkhuu and Takao Hamakubo and Hiroko Iwanari and Senlin Li and Christman, {John W.} and Saran Shantikumar and Angelini, {Gianni D.} and Costanza Emanueli and Masuko Fukai and Tohru Fukai",
year = "2015",
month = "10",
day = "6",
doi = "10.1038/srep14780",
language = "English (US)",
volume = "5",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Copper Transport Protein Antioxidant-1 Promotes Inflammatory Neovascularization via Chaperone and Transcription Factor Function

AU - Chen, Gin Fu

AU - Varadarajan, Sudhahar

AU - Youn, Seock Won

AU - Das, Archita

AU - Cho, Jaehyung

AU - Kamiya, Tetsuro

AU - Urao, Norifumi

AU - McKinney, Ronald D.

AU - Surenkhuu, Bayasgalan

AU - Hamakubo, Takao

AU - Iwanari, Hiroko

AU - Li, Senlin

AU - Christman, John W.

AU - Shantikumar, Saran

AU - Angelini, Gianni D.

AU - Emanueli, Costanza

AU - Fukai, Masuko

AU - Fukai, Tohru

PY - 2015/10/6

Y1 - 2015/10/6

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84943267917&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84943267917&partnerID=8YFLogxK

U2 - 10.1038/srep14780

DO - 10.1038/srep14780

M3 - Article

VL - 5

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

M1 - 14780

ER -