Role of copper transport protein antioxidant 1 in angiotensin ii-induced hypertension: A key regulator of extracellular superoxide dismutase

Kiyoshi Ozumi, Varadarajan Sudhahar, Ha Won Kim, Gin Fu Chen, Takashi Kohno, Lydia Finney, Stefan Vogt, Ronald D. McKinney, Masuko Ushio-Fukai, Tohru Fukai

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)476-486
Number of pages11
JournalHypertension
Volume60
Issue number2
DOIs
StatePublished - Aug 2012

Keywords

  • SOD1
  • SOD3
  • angiotensin II
  • antioxidant 1
  • copper
  • hypertension
  • oxidative stress

ASJC Scopus subject areas

  • Internal Medicine

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