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(Hypertension. 2005;46:1147.)
© 2005 American Heart Association, Inc.

Original Articles

Critical Role for CuZn-Superoxide Dismutase in Preventing Angiotensin II-Induced Endothelial Dysfunction

From the Departments of Internal Medicine (S.P.D., D.A.K., F.M.F.) and Pharmacology (F.M.F.), Cardiovascular Center, The University of Iowa Carver College of Medicine, Iowa City.

Correspondence to Sean P. Didion, PhD, Department of Internal Medicine, The University of Iowa Carver College of Medicine, Iowa City, IA 52242. E-mail sean-didion{at}uiowa.edu

The goal of the present study was to test the hypothesis that the CuZn isoform of superoxide dismutase (CuZnSOD) protects against angiotensin II (Ang II)–induced endothelial dysfunction. Vascular responses of carotid arteries from control, CuZnSOD-deficient (CuZnSOD^+/–), and CuZnSOD transgenic mice were examined in vitro after overnight incubation with either vehicle or Ang II (1 or 10 nmol/L). In control mice, acetylcholine produced concentration-dependent relaxation that was not affected by 1 nmol/L Ang II. In contrast, relaxation to acetylcholine in arteries from CuZnSOD+/– mice was markedly and selectively attenuated after incubation with 1 nmol/L Ang II (eg, 100 µmol/L acetylcholine produced 93±6% and 44±15% relaxation in vehicle- and Ang II-treated arteries, respectively). A higher concentration of Ang II (10 nmol/L) selectively impaired relaxation to acetylcholine in arteries from control mice (eg, 100 µmol/L acetylcholine produced 96±4% and 45±7% relaxation in vehicle- and Ang II-treated vessels, respectively). In contrast, 10 nmol/L Ang II had no effect on responses to acetylcholine in carotid arteries from CuZnSOD transgenic mice (or in control mice treated with the superoxide scavenger Tiron [1 mmol/L]). Superoxide levels in control mice were higher in aorta treated with Ang II than with vehicle and were markedly reduced in CuZnSOD transgenic mice. These findings provide the first direct evidence that CuZnSOD limits Ang II-mediated impairment of endothelial function and that loss of 1 copy of the CuZnSOD gene is sufficient to enhance Ang II-induced vascular dysfunction.

Key Words: mice • oxidative stress • endothelium • vessels

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