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(Hypertension. 2003;42:997.)
© 2003 American Heart Association, Inc.

Scientific Contributions

Endothelin-1 Stimulates Arterial VCAM-1 Expression Via NADPH Oxidase-Derived Superoxide in Mineralocorticoid Hypertension

Lixin Li; Yi Chu; Gregory D. Fink; John F. Engelhardt; Donald D. Heistad; Alex F. Chen

From the Department of Pharmacology and Toxicology and the Neuroscience Program (L.L, G.D.F., A.F.C.), Michigan State University, East Lansing; and the Departments of Medicine (Y.C., J.F.E., D.D.H.) and Anatomy and Cell Biology (J.F.E.), University of Iowa, Iowa City.

Correspondence to Dr Alex F. Chen, Department of Pharmacology and Toxicology, B403 Life Sciences Bldg, Michigan State University, East Lansing, MI 48824-1317. E-mail chenal{at}msu.edu

Although hypertension is a major risk factor for atherosclerosis, its underlying mechanisms remain to be delineated. We have recently reported that both endothelin-1 (ET-1) and vascular cellular adhesion molecule-1 (VCAM-1) levels, key early markers of atherosclerosis, are significantly elevated in carotid arteries of deoxycorticosterone acetate (DOCA)-salt hypertensive rats, a model known for its suppressed plasma renin levels. This study tested the hypothesis that ET-1 augments arterial VCAM-1 expression through NADPH oxidase-derived superoxide (O₂^-). Carotid arteries of DOCA-salt or sham-operated rats were transduced ex vivo with extracellular superoxide dismutase (EC-SOD), dominant negative HA-tagged N17Rac1 that inhibits Rac1, the small GTPase component of NADPH oxidase, or ß-galactosidase (ß-gal) reporter gene (5x10¹⁰ plaque formation units [pfu]/mL), and the effect of transgene expression on O₂^- and VCAM-1 levels was assayed 24 hours afterward. The arterial activity of NADPH oxidase but not xanthine oxidase was significantly higher in DOCA-salt than in sham rats, which was abolished by the selective ET_A receptor antagonist ABT-627 (3x10^-8 mol/L), NADPH oxidase inhibitor apocynin (10^-4 mol/L), or dominant negative Rac1 gene transfer. The levels of O₂^- and VCAM-1 were significantly increased in arteries of DOCA-salt rats, an effect that was ameliorated after EC-SOD or dominant negative Rac1 but not ß-gal reporter gene transfer. ABT-627 and apocynin also significantly reduced elevated VCAM-1 levels in ET-1-treated arteries of normal rats and arteries of DOCA-salt rats. The results of this study indicate that ET-1 stimulates arterial VCAM-1 expression by producing O₂^- from an ET_A receptor/NADPH oxidase pathway in low-renin mineralocorticoid hypertension.

Key Words: endothelin • atherosclerosis • hypertension, mineralocorticoid • oxidative stress

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