Role of menkes ATpase in angiotensin II-induced hypertension: A key modulator for extracellular superoxide dismutase function

Zhenyu Qin, Maria Carolina Gongora, Kiyoshi Ozumi, Shinichi Itoh, Kamran Akram, Masuko Ushio-Fukai, David G. Harrison, Tohru Fukai

Research output: Contribution to journalArticle

40 Scopus citations

Abstract

The extracellular superoxide dismutase (SOD3), a secretory copper-containing enzyme, regulates angiotensin II (Ang II)-induced hypertension by modulating levels of extracellular superoxide anion. The present study was designed to determine the role of the copper transporter Menkes ATPase (MNK) in Ang II-induced SOD3 activity and hypertension in vivo. Here we show that chronic Ang II infusion enhanced systolic blood pressure and vascular superoxide anion production in MNK mutant (MNKmut) mice as compared with those in wild-type mice, which are associated with impaired acetylcholine-induced endothelium-dependent vasorelaxation in MNKmut mice. These effects in MNKmut mice are rescued by infusion of the SOD mimetic Tempol. By contrast, norepinephrine-induced hypertension, which is not associated with an increase in vascular superoxide anion production, is not affected in MNK mut mice. Mechanistically, basal and Ang II infusion-induced increase in vascular SOD3-specific activity is significantly inhibited in MNK mut mice. Coimmunoprecipitation analysis reveals that Ang II stimulation promotes association of MNK with SOD3 in cultured vascular smooth muscle cell and in mouse aortas, which may contribute to SOD3-specific activity by increasing copper delivery to SOD3 through MNK. In summary, MNK plays an important role in modulating Ang II-induced hypertension and endothelial function by regulating SOD3 activity and vascular superoxide anion production and becomes a potential therapeutic target for oxidant stress-dependent cardiovascular diseases.

Original languageEnglish (US)
Pages (from-to)945-951
Number of pages7
JournalHypertension
Volume52
Issue number5
DOIs
StatePublished - Nov 1 2008
Externally publishedYes

Keywords

  • Angiotensin ii
  • Hypertension
  • Mnk protein
  • Norepinephrine
  • Oxidative stress
  • SOD1
  • SOD3

ASJC Scopus subject areas

  • Internal Medicine

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