期刊
SCIENTIFIC REPORTS
卷 5, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/srep14780
关键词
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资金
- NIH [R01 HL070187, R01 HL077524, HL077524-S1, R21HL112293]
- Department of Veterans Affairs Merit Review grant [1I01BX001232]
- Ruth L. Kirschstein-National Service Research Award (Kirschstein-NRSA) T32 Training Grant
- AHA [09POST2250151, 11POST5740006]
- [R01HL116976]
- British Heart Foundation [FS/10/61/28566] Funding Source: researchfish
- Grants-in-Aid for Scientific Research [24108007] Funding Source: KAKEN
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 TNF alpha. 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-NF kappa B-VCAM-1/ICAM-1 expression and monocyte adhesion in ECs inflamed with TNFa 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.
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