Novel role of copper transport protein antioxidant-1 in neointimal formation after vascular injury.
OBJECTIVE
Vascular smooth muscle cell (VSMC) migration is critically important for neointimal formation after vascular injury and atherosclerosis lesion formation. Copper (Cu) chelator inhibits neointimal formation, and we previously demonstrated that Cu transport protein antioxidant-1 (Atox1) is involved in Cu-induced cell growth. However, role of Atox1 in VSMC migration and neointimal formation after vascular injury is unknown.


RESULTS
Here, we show that Atox1 expression is upregulated in injured vessel, and it is colocalized with the Cu transporter ATP7A, one of the downstream targets of Atox1, mainly in neointimal VSMCs at day 14 after wire injury. Atox1(-/-) mice show inhibition of neointimal formation and extracellular matrix expansion, which is associated with a decreased VSMCs accumulation within neointima and lysyl oxidase activity. Mechanistically, in cultured VSMC, Atox1 depletion with siRNA inhibits platelet-derived growth factor-induced Cu-dependent VSMC migration by preventing translocation of ATP7A and small G protein Rac1 to the leading edge, as well as Cu- and Rac1-dependent lamellipodia formation. Furthermore, Atox1(-/-) mice show decreased perivascular macrophage infiltration in wire-injured vessels, as well as thioglycollate-induced peritoneal macrophage recruitment.


CONCLUSIONS
Atox1 is involved in neointimal formation after vascular injury through promoting VSMC migration and inflammatory cell recruitment in injured vessels. Thus, Atox1 is a potential therapeutic target for VSMC migration and inflammation-related vascular diseases.
Department of Medicine, Center for Cardiovascular Research, University of Illinois at Chicago, 835 S. Wolcott, M/C868, E403 MSB, Chicago, IL 60612, USA.
Takashi
T
Kohno
Norifumi
N
Urao
Takashi
T
Ashino
Varadarajan
V
Sudhahar
Ronald D
RD
McKinney
Takao
T
Hamakubo
Hiroko
H
Iwanari
Masuko
M
Ushio-Fukai
Tohru
T
Fukai
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D027682:Cation Transport Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement; D002478:Cells, Cultured; D003300:Copper / Q000378:metabolism*; D000079922:Copper Transport Proteins; D000073840:Copper-Transporting ATPases; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism; D005263:Femoral Artery / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D006801:Humans; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000276:immunology / Q000293:injuries / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D058426:Neointima; D009479:Neuropeptides / Q000378:metabolism; D010538:Peritonitis / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D021381:Protein Transport; D008249:Protein-Lysine 6-Oxidase / Q000378:metabolism; D011554:Pseudopodia / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D013864:Thioglycolates; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation; D057772:Vascular System Injuries / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D020830:rac1 GTP-Binding Protein
C499247:Atox1 protein, mouse; C486201:Atp7a protein, mouse; D027682:Cation Transport Proteins; D000079922:Copper Transport Proteins; D018832:Molecular Chaperones; D009479:Neuropeptides; D010982:Platelet-Derived Growth Factor; C484602:Rac1 protein, mouse; D013864:Thioglycolates; C017487:2-mercaptoacetate; D003300:Copper; D008249:Protein-Lysine 6-Oxidase; D000251:Adenosine Triphosphatases; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D000073840:Copper-Transporting ATPases