title: Gadd45α as an upstream signaling molecule of p38 MAPK triggers oxidative stress-induced sFlt-1 and sEng upregulation in preeclampsia.
abstract: Preeclampsia (PE) is known to be associated with increased circulating levels of anti-angiogenic factors, such as soluble fms-related tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng). However, the way that placental oxidative stress results in the elevation of these two factors remains enigmatic. We have observed the overexpression of growth arrest and DNA damage-inducible 45 alpha (Gadd45α) and excessive activation of p38 mitogen-activated protein kinase (MAPK) in preeclamptic placentas compared with normotensive controls, together with increased levels of sFlt-1 and sEng in maternal sera in patients with PE. Moreover, Gadd45α knockdown or p38 inhibition provides protective effects in hypoxia/reoxygenation (H/R)-exposed human umbilical vein endothelial cells (HUVECs) by suppressing oxidative stress, inhibiting apoptosis, and promoting their potential for in vitro angiogenesis. A regulatory signaling pathway in which H/R intervention causes the induction of Gadd45α leading to p38 activation and ultimately an increase in sFlt-1 and sEng secretion in HUVECs has concurrently been established. Our study opens up a promising new avenue of investigation for increasing the understanding of the origin of sFlt-1 and sEng in PE and provides novel therapeutic targets for pregnancy complications arising from placental endothelial dysfunction.
authors.affiliation: Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People's Republic of China.
authors.forename: Xin
authors.initials: X
authors.lastname: Luo
authors.forename: Zhen-wei
authors.initials: ZW
authors.lastname: Yao
authors.forename: Hong-bo
authors.initials: HB
authors.lastname: Qi
authors.forename: Dan-dan
authors.initials: DD
authors.lastname: Liu
authors.forename: Guo-qing
authors.initials: GQ
authors.lastname: Chen
authors.forename: Shuai
authors.initials: S
authors.lastname: Huang
authors.forename: Qing-shu
authors.initials: QS
authors.lastname: Li
mesh_terms: D000328:Adult; D015703:Antigens, CD / Q000097:blood / Q000378:metabolism*; D017209:Apoptosis / Q000502:physiology; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015687:Cell Hypoxia / Q000502:physiology; D000071063:Endoglin; D042783:Endothelial Cells / Q000378:metabolism; D004789:Enzyme Activation; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D007150:Immunohistochemistry; D020935:MAP Kinase Signaling System; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D011225:Pre-Eclampsia / Q000097:blood / Q000201:enzymology / Q000378:metabolism*; D011247:Pregnancy; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000097:blood / Q000378:metabolism*; D014162:Transfection; D015854:Up-Regulation; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000097:blood / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000097642:GADD45 Proteins
chemical_list: D015703:Antigens, CD; D018797:Cell Cycle Proteins; D000071063:Endoglin; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D011956:Receptors, Cell Surface; D040281:Vascular Endothelial Growth Factor Receptor-1; D048051:p38 Mitogen-Activated Protein Kinases; C064206:ENG protein, human; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C501162:FLT1 protein, human