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(Circulation. 2004;110:1612-1619.)
© 2004 American Heart Association, Inc.

Hypertension

Antibodies From Preeclamptic Patients Stimulate Increased Intracellular Ca²⁺ Mobilization Through Angiotensin Receptor Activation

Theingi M. Thway, PhD; Sergiy G. Shlykov, PhD; Mary-Clare Day, BSN; Barbara M. Sanborn, PhD; Larry C. Gilstrap, III, MD; Yang Xia, MD, PhD; Rodney E. Kellems, PhD

From the Departments of Biochemistry and Molecular Biology (T.M.T., S.G.S., B.M.S., Y.X., R.E.K.) and Obstetrics, Gynecology, and Reproductive Sciences (M.-C.D., L.C.G.), The University of Texas Health Science Center at Houston.

Correspondence to Dr Rodney E. Kellems, Department of Biochemistry and Molecular Biology, University of Texas Health Science Center at Houston, 6431 Fannin St, Houston, TX 77030. E-mail rodney.e.kellems{at}uth.tmc.edu

Received October 23, 2003; de novo received March 22, 2004; revision received June 1, 2004; accepted June 23, 2004.

Background— Preeclampsia is a serious disorder of pregnancy characterized by hypertension, proteinuria, edema, and coagulation and vascular abnormalities. At the cellular level, abnormalities include increased calcium concentration in platelets, lymphocytes, and erythrocytes. Recent studies have shown that antibodies directed against angiotensin II type I (AT₁) receptors are also highly associated with preeclampsia.

Methods and Results— We tested the hypothesis that AT₁ receptor–agonistic antibodies (AT₁-AAs) could activate AT₁ receptors, leading to an increased intracellular concentration of free calcium and to downstream activation of Ca²⁺ signaling pathways. Sera of 30 pregnant patients, 16 diagnosed with severe preeclampsia and 14 normotensive, were examined for the presence of IgG capable of stimulating intracellular Ca²⁺ mobilization. IgG from all preeclamptic patients activated AT₁ receptors and increased intracellular free calcium. In contrast, none of the normotensive individuals had IgG capable of activating AT₁ receptors. The specific mobilization of intracellular Ca²⁺ by AT₁-AAs was blocked by losartan, an AT₁ receptor antagonist, and by a 7-amino-acid peptide that corresponds to a portion of the second extracellular loop of the AT₁ receptor. In addition, we have shown that AT₁-AA–stimulated mobilization of intracellular Ca²⁺ results in the activation of the transcription factor, nuclear factor of activated T cells.

Conclusions— These results suggest that maternal antibodies capable of activating AT₁ receptors are likely to account for increased intracellular free Ca²⁺ concentrations and changes in gene expression associated with preeclampsia.

Key Words: autoimmunity • antibodies • signal transduction • hypertension • pregnancy

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