Published Online
on September 2, 2008

A more recent version of this article appeared on November 1, 2008

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Submitted on May 18, 2008
Revised on June 4, 2008

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; and Tohru Fukai^*

From the Division of Cardiology, Department of Medicine (Z.Q., M.C.G., S.T., K.A., M.U.-F., D.G.H., T.F.), Emory University, School of Medicine, Atlanta, Ga; and the Departments of Medicine (Section of Cardiology) and Pharmacology (K.O., T.F.), Center for Cardiovascular Research and the Department of Pharmacology (M.U.-F.), University of Illinois at Chicago.

^* To whom correspondence should be addressed. E-mail: tfukai{at}uic.edu.

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 (MNK^mut) mice as compared with those in wild-type mice, which are associated with impaired acetylcholine-induced endothelium-dependent vasorelaxation in MNK^mut mice. These effects in MNK^mut 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.

Key words: angiotensin II • hypertension • MNK protein • norepinephrine • oxidative stress • SOD1 • SOD3

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