title: Role of copper transport protein antioxidant 1 in angiotensin II-induced hypertension: a key regulator of extracellular superoxide dismutase.
abstract: Extracellular superoxide dismutase (SOD3) is a secretory copper enzyme involved in protecting angiotensin II (Ang II)-induced hypertension. We found previously that Ang II upregulates SOD3 expression and activity as a counterregulatory mechanism; however, underlying mechanisms are unclear. Antioxidant 1 (Atox1) is shown to act as a copper-dependent transcription factor, as well as a copper chaperone, for SOD3 in vitro, but its role in Ang II-induced hypertension in vivo is unknown. Here we show that Ang II infusion increases Atox1 expression, as well as SOD3 expression and activity, in aortas of wild-type mice, which are inhibited in mice lacking Atox1. Accordingly, Ang II increases vascular superoxide production, reduces endothelium-dependent vasodilation, and increases vasoconstriction in mesenteric arteries to a greater extent in Atox1(-/-) than in wild-type mice. This contributes to augmented hypertensive response to Ang II in Atox1(-/-) mice. In cultured vascular smooth muscle cells, Ang II promotes translocation of Atox1 to the nucleus, thereby increasing SOD3 transcription by binding to Atox1-responsive element in the SOD3 promoter. Furthermore, Ang II increases Atox1 binding to the copper exporter ATP7A, which obtains copper from Atox1, as well as translocation of ATP7A to plasma membranes, where it colocalizes with SOD3. As its consequence, Ang II decreases vascular copper levels, which is inhibited in Atox1(-/-) mice. In summary, Atox1 functions to prevent Ang II-induced endothelial dysfunction and hypercontraction in resistant vessels, as well as hypertension, in vivo by reducing extracellular superoxide levels via increasing vascular SOD3 expression and activity.
authors: Department of Medicine, Center for Cardiovascular Research, Center for Lung and Vascular Biology, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors: Kiyoshi
authors: K
authors: Ozumi
authors: Varadarajan
authors: V
authors: Sudhahar
authors: Ha Won
authors: HW
authors: Kim
authors: Gin-Fu
authors: GF
authors: Chen
authors: Takashi
authors: T
authors: Kohno
authors: Lydia
authors: L
authors: Finney
authors: Stefan
authors: S
authors: Vogt
authors: Ronald D
authors: RD
authors: McKinney
authors: Masuko
authors: M
authors: Ushio-Fukai
authors: Tohru
authors: T
authors: Fukai
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000804:Angiotensin II / Q000009:adverse effects* / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D027682:Cation Transport Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D003300:Copper / Q000378:metabolism; D000079922:Copper Transport Proteins; D000073840:Copper-Transporting ATPases; D004195:Disease Models, Animal; D005260:Female; D006973:Hypertension / Q000139:chemically induced* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010100:Oxygen / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism*
chemical_list: C499247:Atox1 protein, mouse; C486201:Atp7a protein, mouse; D027682:Cation Transport Proteins; D000079922:Copper Transport Proteins; D018832:Molecular Chaperones; D000804:Angiotensin II; D003300:Copper; C499090:Sod3 protein, mouse; D013482:Superoxide Dismutase; D000251:Adenosine Triphosphatases; D000073840:Copper-Transporting ATPases; D010100:Oxygen