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Role of Copper Transport System for Extracellular Superoxide Dismutase in Angiotensin II‐Induced Hypertension
Author(s) -
Fukai Tohru,
Ozumi Kiyoshi,
Kim Ha Won,
McKinney Ronald D.,
UshioFukai Masuko
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.231.3
Subject(s) - angiotensin ii , extracellular , chemistry , superoxide dismutase , downregulation and upregulation , vascular smooth muscle , transcription factor , endocrinology , medicine , superoxide , dismutase , microbiology and biotechnology , enzyme , biology , biochemistry , receptor , gene , smooth muscle
Vascular extracellular superoxide dismutase (SOD3), a secretory copper enzyme, blunts angiotensin II (Ang II)‐induced hypertension by reducing the extracellular superoxide (O2▸‐) levels. We previously demonstrated that Ang II upregulates SOD3 expression and activity; however, underlying molecular mechanisms remain unclear. Here we show that SOD3 expression and activity are markedly decreased in fibroblasts lacking the copper chaperone/transcription factor Atox1 or the copper uptake transporter Ctr1. Chronic Ang II infusion increases nuclear staining of Atox1 as well as SOD3 protein expression and activity in mouse aorta, which are abolished in Atox1‐deficient (Atox1‐KO) mice. In cultured vascular smooth muscle cells, Ang II stimulates nuclear translocation of Atox1 and SOD3 promoter activity through its binding to the Atox1 responsive element, which are abolished in cells lacking Ctr1. Finally, Atox1‐KO mice infused with Ang II show enhanced systolic blood pressure as well as vascular O2▸‐ levels, which are rescued by the SOD mimetic tempol. In summary, copper‐dependent transcription factor function of Atox1 plays an important role in Ang II‐induced upregulation of SOD3 expression and activity through Ctr1‐Atox1 pathway, which may contribute to preventing oxidant‐stress‐dependent Ang II‐induced hypertension. This work was supported by 5R01HL070187‐08.