TY - JOUR
T1 - Copper Transport Protein Antioxidant-1 Promotes Inflammatory Neovascularization via Chaperone and Transcription Factor Function
AU - Chen, Gin Fu
AU - Sudhahar, Varadarajan
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 - Ushio-Fukai, Masuko
AU - Fukai, Tohru
N1 - Funding Information:
We acknowledge Dr. Michael Simons and Dr. Zhenwu Zhuang in Yale University for generously providing Bismuth contrast reagent for Micro-CT experiment. We also acknowledge Dr. Rick Sumner, Dr. Ryan Rose and microCT/Histology core in Rush University for Micro-CT study. We thank Dr. Robert Clark51 in University of Texas Health Science Center for providing p47phox promoter-reporter constructs as well as Dr. Lance Terada in University of Texas Southwestern for providing p47phox-EGFP construct. SS is a British Heart Foundation (BHF) PhD student; GDA is BHF Chair in cardiac surgery and NIHR Senior Investigator; CE is a BHF Senior Research Fellow. Sources of Funding: This research was supported by NIH R01 HL070187 (T.F.), Department of Veterans Affairs Merit Review grant 1I01BX001232 (T.F.), R01HL116976 (T.F., M.U.-F.), NIH R01 HL077524 and HL077524-S1, R21HL112293 (to M.U.-F.), Ruth L. Kirschstein-National Service Research Award (Kirschstein-NRSA) T32 Training Grant (to G-F.C.), AHA Post-doctoral Fellowship 09POST2250151 (to N.U.), and 11POST5740006 (to V.S.).
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
U2 - 10.1038/srep14780
DO - 10.1038/srep14780
M3 - Article
C2 - 26437801
AN - SCOPUS:84943267917
SN - 2045-2322
VL - 5
JO - Scientific reports
JF - Scientific reports
M1 - 14780
ER -