Arteriosclerosis, Thrombosis, and Vascular Biology. 2002;22:1845-1851
Published online before print August 29, 2002, doi: 10.1161/01.ATV.0000035392.38687.65
Published online before print August 29, 2002, doi: 10.1161/01.ATV.0000035392.38687.65
© 2002 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Dose-Dependent Regulation of NAD(P)H Oxidase Expression by Angiotensin II in Human Endothelial Cells
Protective Effect of Angiotensin II Type 1 Receptor Blockade in Patients With Coronary Artery Disease
From the Institute of Pathophysiology (U.R., J.H., H.M.) and the Julius-Bernstein-Institute of Physiology (U.R.), Martin Luther University Halle-Wittenberg, Halle, Germany, and the Department of Veterinary Molecular Biology (M.T.Q.), Montana State University, Bozeman.
Correspondence to Henning Morawietz, PhD, Institute of Pathophysiology, Faculty of Medicine, Martin Luther University Halle-Wittenberg, Magdeburger Str. 18, D-06097 Halle, Germany. E-mail henning.morawietz{at}medizin.uni-halle.de
Objective— Angiotensin II (Ang II)–mediated induction of vascular superoxide anion formation could contribute to the development of endothelial dysfunction, hypertension, and atherosclerosis. An NAD(P)H oxidase has been identified as a major endothelial source of superoxide anions. However, the molecular mechanism underlying the regulation of NAD(P)H oxidase activity in response to Ang II is not well understood.
Methods and Results— We investigated the dose-dependent regulation of superoxide anion formation and of NAD(P)H oxidase subunit expression in response to Ang II in human endothelial cells. Ang II regulates superoxide anion formation and the limiting subunit of endothelial NAD(P)H oxidase, gp91-phox, in a dose-dependent manner via Ang II type 1 (AT1) receptor–mediated induction and Ang II type 2 receptor–mediated partial inhibition at higher Ang II concentrations. Furthermore, AT1 receptor blocker therapy before coronary bypass surgery downregulates the gp91-phox expression in internal mammary artery biopsies of patients with coronary artery disease.
Conclusions— Our data support a dose-dependent induction of proatherosclerotic oxidative stress in human endothelial cells in response to Ang II. The expression of NAD(P)H oxidase subunit gp91-phox is critical for endothelial superoxide anion formation. AT1 receptor blockade has an antiatherosclerotic and antioxidative potential by the reduction of oxidative stress in the vessel wall.
Key Words: angiotensin • atherosclerosis • cardiopulmonary bypass • endothelium • free radicals
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