Abstract 205: Tissue Transglutaminase as a Novel Pathogenic Factor and Therapeutic Target for Preeclampsia
Preeclampsia (PE) is a prevalent life-threatening complication of pregnancy featuring hypertension, placental abnormality, and renal damage. The condition is associated with the presence of agonistic autoantibodies (AT1-AA) capable of activating the major angiotensin receptor, AT1R, and believed to contribute to disease pathogenesis. Tissue transglutaminase (tTG), a prominent member of a family of enzymes that crosslink proteins by catalyzing the formation of inter- or intra-molecular ε-(γ-glutamyl)-lysine isopeptide bonds, is known to interact with G protein-coupled receptors and contribute to hypertension. Thus, we hypothesize that AT1-AA may function via tTG to crosslink AT1R and contribute to pathophyhsiology of PE. To test this hypothesis, using immunoprecipation with anti-tTG antibody, we successfully pulled down more AT1R from human trophoblast (HTR) cells treated with IgG from PE women than IgG from normotensive (NT) women, thereby providing initial evidence for the promotional effect of AT1-AA on tTG and AT1R interaction. Subsequently, we measured tTG and its modification on AT1R in both NT and PE placentas. We found increased levels of tissue transglutaminase (∼2 folds), ε-(γ-glutamyl)-lysine isopeptides (∼2 folds), and AT1R with ε-(γ-glutamyl)-lysine isopeptide bonds at the microvillous membrane of PE placentas, indicating that tTG-induced AT1 receptor modification is elevated in PE placenta. Finally, in an effort to determine the role of elevated tTG in AT1-AA-induced PE in vivo, we treated PE-IgG injected pregnant mice with cystamine, a potent tTG inhibitor. Compared with PE-IgG injected mice, less AT1 receptor with ε-(γ-glutamyl)-lysine isopeptide bonds was found in the placental labyrinth zone of PE-IgG injected mice treated with cystamine. Moreover, cystamine treatment significantly attenuated key features associated with PE including hypertension (from 159.5±5.6 to 132.6±2.7 mm Hg) and proteinuria (from 106.5±37.8 to 38.5±6.9 ng albumin/mg creatine) in the PE-IgG-injected pregnant mice as well. Taken together, here we report a previously unrecognized role of tTG in the pathogenesis of PE by crosslinking AT1Rs and suggest a novel therapeutics for the disease.
- © 2012 by American Heart Association, Inc.