This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dechend, R. Articles by Luft, F. C. Search for Related Content PubMed PubMed Citation Articles by Dechend, R. Articles by Luft, F. C. Related Collections ACE/Angiotension receptors Other hypertension Gene expression Other diagnostic testing Coagulation and fibronolysis Other Vascular biology

(Circulation. 2000;101:2382.)
© 2000 American Heart Association, Inc.

Clinical Investigation and Reports

AT₁ Receptor Agonistic Antibodies From Preeclamptic Patients Cause Vascular Cells to Express Tissue Factor

Ralf Dechend, MD; Volker Homuth, MD; Gerd Wallukat, PhD; Jörg Kreuzer, MD; Jeun Koon Park, PhD; Jürgen Theuer, MD; Axel Juepner, MD; Dietrich C. Gulba, MD; Nigel Mackman, PhD; Hermann Haller, MD; Friedrich C. Luft, MD

From Franz Volhard Clinic and Max Delbrück Center for Molecular Medicine, Medical Faculty of the Charité, Humboldt University of Berlin (Germany) (R.D., V.H., J.-K.P, J.T., D.C.G., H.H., F.C.L); the Department of Obstetrics and Gynecology, Klinikum Buch, Berlin, Germany (A.J.); the Department of Internal Medicine III, University of Heidelberg (Germany) (J.K.); and the Department of Immunology and Vascular Biology, Scripps Institute, La Jolla, Calif (N.M.).

Correspondence to Friedrich C. Luft, Franz Volhard Clinic, Charité Campus-Buch, Wiltberg Strasse 50, 13125 Berlin, Germany. E-mail luft{at}fvk-berlin.de

Background—We recently described autoantibodies (angiotensin-1 receptor autoantibodies, AT₁-AA) directed at the AT₁ receptor in the serum of preeclamptic patients, whose placentas are commonly infarcted and express tissue factor (TF). Mechanisms of how AT₁-AA might contribute to preeclampsia are unknown. We tested the hypothesis that AT₁-AA cause vascular smooth muscle cells (VSMC) to express TF.

Methods and Results—IgG from preeclamptic patients containing AT₁-AA was purified with anti-human IgG columns. AT₁-AA were separated from the IgG by ammonium sulfate precipitation. We transfected Chinese hamster ovary cells overexpressing the AT₁ receptor with TF promoter constructs coupled to a luciferase reporter gene. VSMC were obtained from human coronary arteries. Extracellular signal-related kinase activation was detected by an in-gel kinase assay. AP-1 activation was determined by electromobility shift assay. TF was measured by ELISA and detected by immunohistochemistry. Placentas from preeclamptic women stained strongly for TF, whereas control placentas showed far less staining. We proved AT₁-AA specificity by coimmunoprecipitating the AT₁ receptor with AT₁-AA but not with nonspecific IgG. Angiotensin (Ang) II and AT₁-AA both activated extracellular signal-related kinase, AP-1, and the TF promoter transfected VSMC and Chinese hamster ovary cells, but only when the AP-1 binding site was present. We then demonstrated TF expression in VSMC exposed to either Ang II or AT₁-AA. All these effects were blocked by losartan. Nonspecific IgG or IgG from nonpreeclamptic pregnant women had a negligible effect.

Conclusions—We conclude that AT₁-AA and Ang II both stimulate the AT₁ receptor and initiate a signaling cascade resulting in TF expression. These results show an action of AT₁-AA on human cells that could contribute to the pathogenesis of preeclampsia.

Key Words: angiotensin • receptors • muscle, smooth • pregnancy

This article has been cited by other articles:

				S. Falcao, E. Stoyanova, G. Cloutier, R. L. Maurice, J. Gutkowska, and J. L. Lavoie Mice Overexpressing Both Human Angiotensinogen and Human Renin as a Model of Superimposed Preeclampsia on Chronic Hypertension Hypertension, December 1, 2009; 54(6): 1401 - 1407. [Abstract] [Full Text] [PDF]

				B. LaMarca, M. Parrish, L. F. Ray, S. R. Murphy, L. Roberts, P. Glover, G. Wallukat, K. Wenzel, K. Cockrell, J. N. Martin Jr, et al. Hypertension in Response to Autoantibodies to the Angiotensin II Type I Receptor (AT1-AA) in Pregnant Rats: Role of Endothelin-1 Hypertension, October 1, 2009; 54(4): 905 - 909. [Abstract] [Full Text] [PDF]

				L. Anton and K. B. Brosnihan Review: Systemic and uteroplacental renin--angiotensin system in normal and pre-eclamptic pregnancies Therapeutic Advances in Cardiovascular Disease, October 1, 2008; 2(5): 349 - 362. [Abstract] [PDF]

				S. A. Karumanchi and M. D. Lindheimer Preeclampsia Pathogenesis: "Triple A Rating"-Autoantibodies and AntiAngiogenic Factors Hypertension, April 1, 2008; 51(4): 991 - 992. [Full Text] [PDF]

				C. C. Zhou, S. Ahmad, T. Mi, S. Abbasi, L. Xia, M.-C. Day, S. M. Ramin, A. Ahmed, R. E. Kellems, and Y. Xia Autoantibody From Women With Preeclampsia Induces Soluble Fms-Like Tyrosine Kinase-1 Production via Angiotensin Type 1 Receptor and Calcineurin/Nuclear Factor of Activated T-Cells Signaling Hypertension, April 1, 2008; 51(4): 1010 - 1019. [Abstract] [Full Text] [PDF]

				M. Mogi, M. Iwai, and M. Horiuchi Emerging Concepts of Regulation of Angiotensin II Receptors: New Players and Targets for Traditional Receptors Arterioscler Thromb Vasc Biol, December 1, 2007; 27(12): 2532 - 2539. [Abstract] [Full Text] [PDF]

				Y. Xia, C. C. Zhou, S. M. Ramin, and R. E. Kellems Angiotensin Receptors, Autoimmunity, and Preeclampsia J. Immunol., September 15, 2007; 179(6): 3391 - 3395. [Abstract] [Full Text] [PDF]

				J. V. Ilekis, U. M. Reddy, and J. M. Roberts Review Article: Preeclampsia A Pressing Problem: An Executive Summary of a National Institute of Child Health and Human Development Workshop Reproductive Sciences, September 1, 2007; 14(6): 508 - 523. [Abstract] [PDF]

				Y. Xia, S. M. Ramin, and R. E. Kellems Potential Roles of Angiotensin Receptor-Activating Autoantibody in the Pathophysiology of Preeclampsia Hypertension, August 1, 2007; 50(2): 269 - 275. [Full Text] [PDF]

				C. A. Hubel, G. Wallukat, M. Wolf, F. Herse, A. Rajakumar, J. M. Roberts, N. Markovic, R. Thadhani, F. C. Luft, and R. Dechend Agonistic Angiotensin II Type 1 Receptor Autoantibodies in Postpartum Women With a History of Preeclampsia Hypertension, March 1, 2007; 49(3): 612 - 617. [Abstract] [Full Text] [PDF]

				F. Herse, R. Dechend, N. K. Harsem, G. Wallukat, J. Janke, F. Qadri, L. Hering, D. N. Muller, F. C. Luft, and A. C. Staff Dysregulation of the Circulating and Tissue-Based Renin-Angiotensin System in Preeclampsia Hypertension, March 1, 2007; 49(3): 604 - 611. [Abstract] [Full Text] [PDF]

				C. C. Zhou, S. Ahmad, T. Mi, L. Xia, S. Abbasi, P. W. Hewett, C. Sun, A. Ahmed, R. E. Kellems, and Y. Xia Angiotensin II Induces Soluble fms-Like Tyrosine Kinase-1 Release via Calcineurin Signaling Pathway in Pregnancy Circ. Res., January 5, 2007; 100(1): 88 - 95. [Abstract] [Full Text] [PDF]

				M. Paul, A. Poyan Mehr, and R. Kreutz Physiology of local Renin-Angiotensin systems. Physiol Rev, July 1, 2006; 86(3): 747 - 803. [Abstract] [Full Text] [PDF]

				R. Dechend, V. Homuth, G. Wallukat, D. N. Muller, M. Krause, J. Dudenhausen, H. Haller, and F. C. Luft Agonistic Antibodies Directed at the Angiotensin II, AT1 Receptor in Preeclampsia Reproductive Sciences, February 1, 2006; 13(2): 79 - 86. [Abstract] [PDF]

				C. Lam, K.-H. Lim, and S. A. Karumanchi Circulating Angiogenic Factors in the Pathogenesis and Prediction of Preeclampsia Hypertension, November 1, 2005; 46(5): 1077 - 1085. [Abstract] [Full Text] [PDF]

				D. M. Shah Role of the renin-angiotensin system in the pathogenesis of preeclampsia Am J Physiol Renal Physiol, April 1, 2005; 288(4): F614 - F625. [Abstract] [Full Text] [PDF]

				R. Dechend, P. Gratze, G. Wallukat, E. Shagdarsuren, R. Plehm, J.-H. Brasen, A. Fiebeler, W. Schneider, S. Caluwaerts, L. Vercruysse, et al. Agonistic Autoantibodies to the AT1 Receptor in a Transgenic Rat Model of Preeclampsia Hypertension, April 1, 2005; 45(4): 742 - 746. [Abstract] [Full Text] [PDF]

				D. Dragun, D. N. Muller, J. H. Brasen, L. Fritsche, M. Nieminen-Kelha, R. Dechend, U. Kintscher, B. Rudolph, J. Hoebeke, D. Eckert, et al. Angiotensin II Type 1-Receptor Activating Antibodies in Renal-Allograft Rejection N. Engl. J. Med., February 10, 2005; 352(6): 558 - 569. [Abstract] [Full Text] [PDF]

				T. M. Thway, S. G. Shlykov, M.-C. Day, B. M. Sanborn, L. C. Gilstrap III, Y. Xia, and R. E. Kellems Antibodies From Preeclamptic Patients Stimulate Increased Intracellular Ca2+ Mobilization Through Angiotensin Receptor Activation Circulation, September 21, 2004; 110(12): 1612 - 1619. [Abstract] [Full Text] [PDF]

				J. M. Davison, V. Homuth, A. Jeyabalan, K. P. Conrad, S. A. Karumanchi, S. Quaggin, R. Dechend, and F. C. Luft New Aspects in the Pathophysiology of Preeclampsia J. Am. Soc. Nephrol., September 1, 2004; 15(9): 2440 - 2448. [Abstract] [Full Text] [PDF]

				R. Thadhani, W. P. Mutter, M. Wolf, R. J. Levine, R. N. Taylor, V. P. Sukhatme, J. Ecker, and S. A. Karumanchi First Trimester Placental Growth Factor and Soluble Fms-Like Tyrosine Kinase 1 and Risk for Preeclampsia J. Clin. Endocrinol. Metab., February 1, 2004; 89(2): 770 - 775. [Abstract] [Full Text] [PDF]

				F. C. Luft Pre-eclampsia and the maternal cardiovascular risk Nephrol. Dial. Transplant., May 1, 2003; 18(5): 860 - 861. [Full Text] [PDF]

				R. Dechend, C. Viedt, D. N. Muller, B. Ugele, R. P. Brandes, G. Wallukat, J.-K. Park, J. Janke, P. Barta, J. Theuer, et al. AT1 Receptor Agonistic Antibodies From Preeclamptic Patients Stimulate NADPH Oxidase Circulation, April 1, 2003; 107(12): 1632 - 1639. [Abstract] [Full Text] [PDF]

				Y. Yia, H. Wne, S. Bobst, M.-C. Day, and R. E. Kellems Maternal Autoantibodies From Preeclamptic Patients Active Angiotensin Receptors on Human Trophoblast Cells Reproductive Sciences, February 1, 2003; 10(2): 82 - 93. [Abstract] [PDF]

				R. A. Khalil and J. P. Granger Vascular mechanisms of increased arterial pressure in preeclampsia: lessons from animal models Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2002; 283(1): R29 - R45. [Abstract] [Full Text] [PDF]

				Y. Xia, H. Y. Wen, and R. E. Kellems Angiotensin II Inhibits Human Trophoblast Invasion through AT1 Receptor Activation J. Biol. Chem., June 28, 2002; 277(27): 24601 - 24608. [Abstract] [Full Text] [PDF]

				J. M. Roberts Angiotensin-1 Receptor Autoantibodies : A Role in the Pathogenesis of Preeclampsia? Circulation, May 23, 2000; 101(20): 2335 - 2337. [Full Text] [PDF]