Agonistic autoantibodies directed against the angiotensin II AT1receptor in patients with preeclampsia

Abstract

We showed that sera from patients with preeclampsia contain autoantibodies directed against the angiotensin II AT1receptor. The antibodies recognize an epitope on the second extracellular loop of the receptor and are immuno globulins of the IgG3 subclass. The antibodies accelerate the beating rate of neonatal rat cardiomyocytes. The agonistic effect can be blocked with the AT1receptor blocker losartan and can be neutralized by a peptide corresponding to the AT1receptor's second extracellular loop. In further studies we shown that the autoantibodies recognize a specific conformation of the AT1receptor. Cleavage of the external disulfide bond with dithiothreitol caused an inactivation of the receptor when stimulated either with Ang II or the autoantibodies in a system of cultured neonatal rat cardiomyocytes. Long-term stimulation of the AT1receptor with either agonists down-regulated the AT1receptor-mediated response to a second Ang II stimulation. These observations show that the agonistic autoantibodies behave pharmacologically in a similar fashion to Ang II. We have found the autoantibodies in all women meeting the clinical criteria of preeclampsia and suggest that they may be important to the pathogenesis of the disease.Key words: angiotensin II, preeclampsia, autoantibodies, IgG subclasses, dithiotrietol, AT1receptor.