Endothelial Antioxidant-1: a Key Mediator of Copper-dependent Wound Healing in vivo.
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 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 important role to sense Cu to accelerate wound angiogenesis and healing.
Departments of Medicine (Section of Cardiology) and Pharmacology, Center for Cardiovascular Research, Center for Lung and Vascular Biology, University of Illinois at Chicago, Chicago IL60612, USA.
Archita
A
Das
Departments of Medicine (Section of Cardiology) and Pharmacology, Center for Cardiovascular Research, Center for Lung and Vascular Biology, University of Illinois at Chicago, Chicago IL60612, USA.|Jesse Brown Veterans Affairs Medical Center, IL60612, Chicago, USA.
Varadarajan
V
Sudhahar
Departments of Medicine (Section of Cardiology) and Pharmacology, Center for Cardiovascular Research, Center for Lung and Vascular Biology, University of Illinois at Chicago, Chicago IL60612, USA.
Gin-Fu
GF
Chen
Departments of Medicine (Section of Cardiology) and Pharmacology, Center for Cardiovascular Research, Center for Lung and Vascular Biology, University of Illinois at Chicago, Chicago IL60612, USA.
Ha Won
HW
Kim
Department of Pharmacology, Center for Lung and Vascular Biology, Center for Cardiovascular Research, University of Illinois at Chicago, Chicago IL60612, USA.
Seock-Won
SW
Youn
X-ray Science Division, Argonne National Laboratory, Argonne, IL60439, USA.
Lydia
L
Finney
X-ray Science Division, Argonne National Laboratory, Argonne, IL60439, USA.
Stefan
S
Vogt
Department of Anesthesiology, University of Wisconsin, Madison, WI 53726, USA.
Jay
J
Yang
Departments of Medicine (Section of Cardiology) and Pharmacology, Center for Cardiovascular Research, Center for Lung and Vascular Biology, University of Illinois at Chicago, Chicago IL60612, USA.|Jesse Brown Veterans Affairs Medical Center, IL60612, Chicago, USA.
Junghun
J
Kweon
Departments of Medicine (Section of Cardiology) and Pharmacology, Center for Cardiovascular Research, Center for Lung and Vascular Biology, University of Illinois at Chicago, Chicago IL60612, USA.|Jesse Brown Veterans Affairs Medical Center, IL60612, Chicago, USA.
Bayasgalan
B
Surenkhuu
Department of Pharmacology, Center for Lung and Vascular Biology, Center for Cardiovascular Research, University of Illinois at Chicago, Chicago IL60612, USA.
Masuko
M
Ushio-Fukai
Departments of Medicine (Section of Cardiology) and Pharmacology, Center for Cardiovascular Research, Center for Lung and Vascular Biology, University of Illinois at Chicago, Chicago IL60612, USA.|Jesse Brown Veterans Affairs Medical Center, IL60612, Chicago, USA.
Tohru
T
Fukai
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