Gadd45a stress signaling regulates sFlt-1 expression in preeclampsia.
Preeclampsia, which affects approximately 5-8% of all pregnancies and is one of the leading causes of maternal and fetal morbidity and mortality, is a pregnancy induced complex of multiple pathological changes, including elevated blood pressure, proteinuria and edema manifested after 20 weeks gestation. There is growing evidence that placental stresses during pregnancy, notably hypoxia, and an increase in circulating soluble Flt-1 (sFlt-1) are important in the etiopathogenesis of preeclampsia. How placental stress results in elevated sFlt-1 expression is currently unknown. Here we provide novel data implicating the Gadd45a stress sensor protein as an upstream modulator of pathophysiological changes observed in preeclampsia. It is shown that Gadd45a expression and activation of its downstream effector p38 kinase are elevated in preeclamptic placentas compared to non-preeclamptic controls, and correlate with elevated sFlt-1. Furthermore, a regulatory loop is demonstrated where stress, including hypoxia, IL-6 or hypertonic stress, caused induction of Gadd45a, leading to p38 activation and ultimately increasing sFlt-1 secretion in endothelial cells. These data provide a compelling working frame to further test the role of Gadd45 stress sensors in the etiology of preeclampsia, and set the stage for considering novel therapeutic regimens, including p38 inhibitors, for treatment of preeclampsia.
Xiong
Yali
Y
Department of Obstetrics & Gynecology, and Reproductive Sciences, Temple University School of Medicine, Philadelphia, Pennsylvania,USA.
Liebermann
Dan A
DA
Tront
Jennifer S
JS
Holtzman
Eliezer J
EJ
Huang
Yajue
Y
Hoffman
Barbara
B
Geifman-Holtzman
Ossie
O
D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D015687:Cell Hypoxia; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D006982:Hypertonic Solutions; D015850:Interleukin-6 / Q000378:metabolism; D048371:MAP Kinase Kinase 3 / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D009997:Osmotic Pressure; D010920:Placenta / Q000201:enzymology / Q000378:metabolism*; D011225:Pre-Eclampsia / Q000201:enzymology / Q000378:metabolism*; D011247:Pregnancy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D013012:Sorbitol / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000097642:GADD45 Proteins
D018797:Cell Cycle Proteins; D006982:Hypertonic Solutions; D015850:Interleukin-6; D048371:MAP Kinase Kinase 3; D009687:Nuclear Proteins; D047428:Protein Kinase Inhibitors; D013012:Sorbitol; D040281:Vascular Endothelial Growth Factor Receptor-1; D048051:p38 Mitogen-Activated Protein Kinases; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C501162:FLT1 protein, human; C482530:MAP2K3 protein, human