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(Circulation. 2003;107:1632.)
© 2003 American Heart Association, Inc.

Clinical Investigation and Reports

AT₁ Receptor Agonistic Antibodies From Preeclamptic Patients Stimulate NADPH Oxidase

Ralf Dechend, MD^*; Christiane Viedt, MD^*; Dominik N. Müller, PhD^*; Bernhard Ugele, PhD; Ralf P. Brandes, MD; Gerd Wallukat, PhD; Joon-Keun Park, PhD; Jurgen Janke, PhD; Peter Barta, MD; Jurgen Theuer, MD; Anette Fiebeler, MD; Volker Homuth, MD; Rainer Dietz, MD; Hermann Haller, MD; Jörg Kreuzer, MD; Friedrich C. Luft, MD

From HELIOS Klinikum-Berlin, Franz Volhard Clinic and the Max Delbrück Center for Molecular Medicine, Humboldt University of Berlin (R.D., D.N.M., G.W., J.J., P.B., J.T., V.H., R.D., F.C.L.); the Department of Internal Medicine III, University of Heidelberg (C.V., J.K.); the Department of Nephrology, Hannover University Medical School, Hannover (J.-K.P., A.F., H.H.); the Department of Obstetrics and Gynecology, Ludwig-Maximillian University, Munich (B.U.); and Physiology, Johann Wolfgang Goethe University Hospital, Frankfurt, Germany (R.P.B.).

Correspondence to Dr Friedrich C. Luft, Wiltberg Strasse 50, 13125 Berlin, Germany. E-mail luft{at}fvk-berlin.de

Background— We recently identified agonistic autoantibodies directed against the angiotensin AT1 receptor (AT₁-AA) in the plasma of preeclamptic women. To elucidate their role further, we studied the effects of AT₁-AA on reactive oxygen species (ROS), NADPH oxidase expression, and nuclear factor-B (NF-B) activation.

Methods and Results— We investigated human vascular smooth muscle cells (VSMC) and trophoblasts, as well as placentas. AT₁-AA were isolated from sera of preeclamptic women. Angiotensin II (Ang II) and AT₁-AA increased ROS production and the NADPH oxidase components, p22, p47, and p67 phox in Western blotting. We next tested if AT₁-AA lead to NF-B activation in VSMC and trophoblasts. AT₁-AA activated NF-B. Inhibitor-B (I-B) expression was reduced in response to AT₁-AA. AT1 receptor blockade with losartan, diphenylene iodonium, tiron, and antisense against p22 phox all reduced ROS production and NF-B activation. VSMC from p47phox-/- mice showed markedly reduced ROS generation and NF-B activation in response to Ang II and AT1-AA. The p22, p47, and p67 phox expression in placentas from preeclamptic patients was increased, compared with normal placentas. Furthermore, NF-B was activated and I-B reduced in placentas from preeclamptic women.

Conclusions— NADPH oxidase is potentially an important source of ROS that may upregulate NF-B in preeclampsia. We suggest that AT₁-AA through activation of NADPH oxidase could contribute to ROS production and inflammatory responses in preeclampsia.

Key Words: receptors, AT₁ • pregnancy • angiotensin • oxygen • cells • antibodies

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