AT 1 Receptor Agonistic Antibodies From Preeclamptic Patients Stimulate NADPH Oxidase

• Published in: Circulation (New York, N.Y.) N.Y.), 2003-04, Vol.107 (12), p.1632-1639
• Main Authors: Dechend, Ralf, Viedt, Christiane, Müller, Dominik N., Ugele, Bernhard, Brandes, Ralf P., Wallukat, Gerd, Park, Joon-Keun, Janke, Jurgen, Barta, Peter, Theuer, Jurgen, Fiebeler, Anette, Homuth, Volker, Dietz, Rainer, Haller, Hermann, Kreuzer, Jörg, Luft, Friedrich C.
• Format: Article
• Language: English
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.CIR.0000058200.90059.B1

Background— We recently identified agonistic autoantibodies directed against the angiotensin AT1 receptor (AT 1 -AA) in the plasma of preeclamptic women. To elucidate their role further, we studied the effects of AT 1 -AA on reactive oxygen species (ROS), NADPH oxidase expression, and nuclear factor-κB (NF-κB) activation. Methods and Results— We investigated human vascular smooth muscle cells (VSMC) and trophoblasts, as well as placentas. AT 1 -AA were isolated from sera of preeclamptic women. Angiotensin II (Ang II) and AT 1 -AA increased ROS production and the NADPH oxidase components, p22, p47, and p67 phox in Western blotting. We next tested if AT 1 -AA lead to NF-κB activation in VSMC and trophoblasts. AT 1 -AA activated NF-κB. Inhibitor-κBα (I-κBα) expression was reduced in response to AT 1 -AA. AT1 receptor blockade with losartan, diphenylene iodonium, tiron, and antisense against p22 phox all reduced ROS production and NF-κB activation. VSMC from p47phox−/− mice showed markedly reduced ROS generation and NF-κB 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-κB was activated and I-κBα reduced in placentas from preeclamptic women. Conclusions— NADPH oxidase is potentially an important source of ROS that may upregulate NF-κB in preeclampsia. We suggest that AT 1 -AA through activation of NADPH oxidase could contribute to ROS production and inflammatory responses in preeclampsia.