Endothelial Antioxidant-1: A Key Mediator of Copper-dependent Wound Healing in vivo

Archita Das, Varadarajan Sudhahar, Gin Fu Chen, Ha Won Kim, Seock Won Youn, Lydia Finney, Stefan Vogt, Jay Yang, Junghun Kweon, Bayasgalan Surenkhuu, Masuko Ushio-Fukai, Tohru Fukai

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Copper (Cu), an essential nutrient, promotes wound healing, however, target of Cu action and underlying mechanisms remain elusive. Cu chaperone Antioxidant-1 (Atox1) in the cytosol supplies Cu to the secretory enzymes such as lysyl oxidase (LOX), while Atox1 in the nucleus functions as a Cu-dependent transcription factor. Using mouse cutaneous wound healing model, here we show that Cu content (by X-ray Fluorescence Microscopy) and nuclear Atox1 are increased after wounding, and that wound healing with and without Cu treatment is impaired in Atox1 -/- mice. Endothelial cell (EC)-specific Atox1 -/- mice and gene transfer of nuclear-target Atox1 in Atox1 -/- mice reveal that Atox1 in ECs as well as transcription factor function of Atox1 are required for wound healing. Mechanistically, Atox1 -/- mice show reduced Atox1 target proteins such as p47phox NADPH oxidase and cyclin D1 as well as extracellular matrix Cu enzyme LOX activity in wound tissues. This in turn results in reducing O 2 â ' production in ECs, NFkB activity, cell proliferation and collagen formation, thereby inhibiting angiogenesis, macrophage recruitment and extracellular matrix maturation. Our findings suggest that Cu-dependent transcription factor/Cu chaperone Atox1 in ECs plays an important role to sense Cu to accelerate wound angiogenesis and healing.

Original languageEnglish (US)
Article number33783
JournalScientific Reports
Volume6
DOIs
StatePublished - Sep 26 2016

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Wound Healing
Copper
Antioxidants
Protein-Lysine 6-Oxidase
Transcription Factors
Extracellular Matrix
NADPH Oxidase
Cyclin D1
Gamma Rays
Enzymes
Fluorescence Microscopy
Cytosol
Collagen
Endothelial Cells
Macrophages
Cell Proliferation
Food
Skin

ASJC Scopus subject areas

  • General

Cite this

Endothelial Antioxidant-1 : A Key Mediator of Copper-dependent Wound Healing in vivo. / Das, Archita; Sudhahar, Varadarajan; Chen, Gin Fu; Kim, Ha Won; Youn, Seock Won; Finney, Lydia; Vogt, Stefan; Yang, Jay; Kweon, Junghun; Surenkhuu, Bayasgalan; Ushio-Fukai, Masuko; Fukai, Tohru.

In: Scientific Reports, Vol. 6, 33783, 26.09.2016.

Research output: Contribution to journalArticle

Das, Archita ; Sudhahar, Varadarajan ; Chen, Gin Fu ; Kim, Ha Won ; Youn, Seock Won ; Finney, Lydia ; Vogt, Stefan ; Yang, Jay ; Kweon, Junghun ; Surenkhuu, Bayasgalan ; Ushio-Fukai, Masuko ; Fukai, Tohru. / Endothelial Antioxidant-1 : A Key Mediator of Copper-dependent Wound Healing in vivo. In: Scientific Reports. 2016 ; Vol. 6.
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abstract = "Copper (Cu), an essential nutrient, promotes wound healing, however, target of Cu action and underlying mechanisms remain elusive. Cu chaperone Antioxidant-1 (Atox1) in the cytosol supplies Cu to the secretory enzymes such as lysyl oxidase (LOX), while Atox1 in the nucleus functions as a Cu-dependent transcription factor. Using mouse cutaneous wound healing model, here we show that Cu content (by X-ray Fluorescence Microscopy) and nuclear Atox1 are increased after wounding, and that wound healing with and without Cu treatment is impaired in Atox1 -/- mice. Endothelial cell (EC)-specific Atox1 -/- mice and gene transfer of nuclear-target Atox1 in Atox1 -/- mice reveal that Atox1 in ECs as well as transcription factor function of Atox1 are required for wound healing. Mechanistically, Atox1 -/- mice show reduced Atox1 target proteins such as p47phox NADPH oxidase and cyclin D1 as well as extracellular matrix Cu enzyme LOX activity in wound tissues. This in turn results in reducing O 2 {\^a} ' production in ECs, NFkB activity, cell proliferation and collagen formation, thereby inhibiting angiogenesis, macrophage recruitment and extracellular matrix maturation. Our findings suggest that Cu-dependent transcription factor/Cu chaperone Atox1 in ECs plays an important role to sense Cu to accelerate wound angiogenesis and healing.",
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