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Novel Role of the ATP7A Copper‐transporting ATPase and Extracellular SOD in Endothelial Dysfunction in Type I Diabetes Mellitus
Author(s) -
Varadarajan Sudhahar,
Urao Norifumi,
Oshikawa Jin,
Llanos Roxana M,
Mckinney Ronald D,
Ushio-Fukai Masuko,
Fukai Tohru
Publication year - 2012
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.26.1_supplement.1057.13
Subject(s) - atp7a , medicine , endocrinology , endothelial dysfunction , extracellular , oxidative stress , superoxide dismutase , chemistry , biology , microbiology and biotechnology , enzyme , atpase , biochemistry
Oxidative stress and endothelial dysfunction contribute to diabetes mellitus (DM). Extracellular superoxide dismutase (ecSOD), a secretory copper enzyme, preserves endothelial function by modulating extracellular superoxide (O 2 •− ) and its full activity requires Cu transporter ATP7A. The present study examines the role of ecSOD and ATP7A in endothelial dysfunction in type 1 DM with hypoinsulinemia. Here we show that specific activity of ecSOD, but not Cu/Zn SOD, is decreased, which is associated with increased O 2 •− production and decrease in ATP7A expression in aortas of streptozotocin induced DM mice. Exogenous copper partially rescued ecSOD activity in isolated DM aortas. Functionally, acetylcholine‐induced NO‐mediated vasorelaxation is impaired in mesenteric arteries of DM, which is rescued by SOD mimetic tempol or adenovirus mediated gene transfer of ecSOD. Mechanistically, insulin application increases activity of ecSOD in hypoinsulinemic DM aortas and also increases ATP7A protein expression in VSMC. Moreover, DM‐induced impaired endothelial function and ecSOD activity are rescued in ATP7A overexpressing transgenic mice. In summary, ATP7A plays an important role in protecting DM induced endothelial dysfunction by regulating ecSOD activity and vascular O 2 •− . Thus, ATP7A is a potential therapeutic target for oxidant stress‐dependent cardiovascular and metabolic diseases. (NIH and AHA).