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Elevated Transglutaminase Activity Triggers Angiotensin Receptor Activating Autoantibody Production and Pathophysiology of Preeclampsia

Elevated Transglutaminase Activity Triggers Angiotensin Receptor Activating Autoantibody Production and Pathophysiology of Preeclampsia

Journal of the American Heart Association 4(12):

Preeclampsia (PE) is a life-threatening hypertensive disorder of pregnancy associated with autoantibodies, termed AT1-AA, that activate the AT1 angiotensin receptor. Although the pathogenic nature of these autoantibodies has been extensively studied, little is known about the molecular cause of their generation. Here we show that tissue transglutaminase (TG2), an enzyme that conducts posttranslational modification of target proteins, directly modified the 7-amino acid (7-aa) epitope peptide that localizes to the second extracellular loop of the AT1 receptor. These findings led us to further discover that plasma transglutaminase activity was induced and contributed to the production of AT1-AA and disease development in an experimental model of PE induced by injection of LIGHT, a tumor necrosis factor superfamily member. Key features of PE were regenerated by adoptive transfer of purified IgG from LIGHT-injected pregnant mice and blocked by the 7-amino acid epitope peptide. Translating our mouse research to humans, we found that plasma transglutaminase activity was significantly elevated in PE patients and was positively correlated with AT1-AA levels and PE features. Overall, we provide compelling mouse and human evidence that elevated transglutaminase underlies AT1-AA production in PE and highlight novel pathogenic biomarkers and innovative therapeutic possibilities for the disease.

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Accession: 057751749

Download citation: RISBibTeXText

PMID: 26675250

DOI: 10.1161/jaha.115.002323

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