title: AT1 receptor agonistic antibodies from preeclamptic patients stimulate NADPH oxidase.
abstract: 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-kappaB (NF-kappaB) activation.
  
  
  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-kappaB activation in VSMC and trophoblasts. AT1-AA activated NF-kappaB. Inhibitor-kappaBalpha (I-kappaBalpha) 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-kappaB activation. VSMC from p47phox-/- mice showed markedly reduced ROS generation and NF-kappaB 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-kappaB was activated and I-kappaBalpha reduced in placentas from preeclamptic women.
  
  
  CONCLUSIONS
  NADPH oxidase is potentially an important source of ROS that may upregulate NF-kappaB in preeclampsia. We suggest that AT1-AA through activation of NADPH oxidase could contribute to ROS production and inflammatory responses in preeclampsia.
authors.affiliation: HELIOS Klinikum-Berlin, Franz Volhard Clinic and the Max Delbrück Center for Molecular Medicine, Humboldt University of Berlin, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Dechend
authors.forename: Christiane
authors.initials: C
authors.lastname: Viedt
authors.forename: Dominik N
authors.initials: DN
authors.lastname: Müller
authors.forename: Bernhard
authors.initials: B
authors.lastname: Ugele
authors.forename: Ralf P
authors.initials: RP
authors.lastname: Brandes
authors.forename: Gerd
authors.initials: G
authors.lastname: Wallukat
authors.forename: Joon-Keun
authors.initials: JK
authors.lastname: Park
authors.forename: Jurgen
authors.initials: J
authors.lastname: Janke
authors.forename: Peter
authors.initials: P
authors.lastname: Barta
authors.forename: Jurgen
authors.initials: J
authors.lastname: Theuer
authors.forename: Anette
authors.initials: A
authors.lastname: Fiebeler
authors.forename: Volker
authors.initials: V
authors.lastname: Homuth
authors.forename: Rainer
authors.initials: R
authors.lastname: Dietz
authors.forename: Hermann
authors.initials: H
authors.lastname: Haller
authors.forename: Jörg
authors.initials: J
authors.lastname: Kreuzer
authors.forename: Friedrich C
authors.initials: FC
authors.lastname: Luft
mesh_terms: D000328:Adult; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001323:Autoantibodies / Q000494:pharmacology*; D002478:Cells, Cultured; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D010920:Placenta / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D011225:Pre-Eclampsia / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism; D011247:Pregnancy; D017382:Reactive Oxygen Species / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000819:agonists / Q000276:immunology*; D014327:Trophoblasts / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism
chemical_list: D001323:Autoantibodies; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D000804:Angiotensin II; D019255:NADPH Oxidases