Endothelial Antioxidant-1: A key mediator of Copper-dependent wound healing in vivo
Abstract
Here, Copper (Cu), an essential nutrient, promotes wound healing, however, target of Cu action and underlying mechanisms remains 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 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. Experiments using 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 O2- 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 essential role to sense Cu to accelerate wound angiogenesis and healing.
- Authors:
-
- Univ. of Illinois at Chicago, Chicago, IL (United States)
- Univ. of Illinois at Chicago, Chicago, IL (United States); Jess Brown Veterans Affairs Medical Center, Chicago, IL (United States)
- Argonne National Lab. (ANL), Argonne, IL (United States)
- Univ. of Wisconsin, Madison, WI (United States)
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States)
- Sponsoring Org.:
- National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES)
- OSTI Identifier:
- 1333007
- Grant/Contract Number:
- AC02-06CH11357
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Scientific Reports
- Additional Journal Information:
- Journal Volume: 6; Journal ID: ISSN 2045-2322
- Publisher:
- Nature Publishing Group
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES
Citation Formats
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, and Fukai, Tohru. Endothelial Antioxidant-1: A key mediator of Copper-dependent wound healing in vivo. United States: N. p., 2016.
Web. doi:10.1038/srep33783.
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. United States. https://doi.org/10.1038/srep33783
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, and Fukai, Tohru. Mon .
"Endothelial Antioxidant-1: A key mediator of Copper-dependent wound healing in vivo". United States. https://doi.org/10.1038/srep33783. https://www.osti.gov/servlets/purl/1333007.
@article{osti_1333007,
title = {Endothelial Antioxidant-1: A key mediator of Copper-dependent wound healing in vivo},
author = {Das, Archita and Sudhahar, Varadarajan and Chen, Gin -Fu and Kim, Ha Won and Youn, Seock -Won and Finney, Lydia and Vogt, Stefan and Yang, Jay and Kweon, Junghun and Surenkhuu, Bayasgalan and Ushio-Fukai, Masuko and Fukai, Tohru},
abstractNote = {Here, Copper (Cu), an essential nutrient, promotes wound healing, however, target of Cu action and underlying mechanisms remains 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 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. Experiments using 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 O2- 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 essential role to sense Cu to accelerate wound angiogenesis and healing.},
doi = {10.1038/srep33783},
journal = {Scientific Reports},
number = ,
volume = 6,
place = {United States},
year = {Mon Sep 26 00:00:00 EDT 2016},
month = {Mon Sep 26 00:00:00 EDT 2016}
}
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