title: Aspirin inhibits expression of sFLT1 from human cytotrophoblasts induced by hypoxia, via cyclo-oxygenase 1.
abstract: BACKGROUND
  Elevated circulating soluble FLT1 (sFLT1) levels seen in preeclampsia may play a role in its development. Aspirin is recommended for prevention of preeclampsia. We hypothesized that aspirin may inhibit the production of sFlt1.
  
  
  METHODS
  Placentas from women with and without preeclampsia were collected. Primary cytotrophoblasts (CTBs) were cultured from normal placentas and treated with aspirin, sc-560, a COX1 inhibitor or celecoxib, a COX2 inhibitor. The expression of sFLT1, FLT1, COX1 and COX2 was studied. The effect of aspirin on sFlt1 expression was also studied in HEK293 cells and in HTR-8/SVNeo cells.
  
  
  RESULTS
  The expression of sFLT1 was increased in preeclamptic placentas compared to control placentas and the expression and release of sFLT1 increased in CTBs exposed to 2% O2 compared to controls. Aspirin at 3 and 12 mM concentration reduced the expression and release of sFLT1 in CTBs. Aspirin also inhibited sFlt1 expression from HTR-8/SVNeo and HEK293 cells. Sc-560, but not celecoxib, reduced sFLT1 expression and release from CTBs. Aspirin and sc-560 also reduced hypoxia-induced FLT1 mRNA expression and inhibited COX1 mRNA in CTBs.
  
  
  CONCLUSIONS
  This study confirms that sFLT1 expression is increased in preeclamptic placentas and in CTBs exposed to hypoxia. Aspirin inhibits the production sFLT1 in CTBs and in HTR-8/SVNeo. Sc-560 recapitulated the effects of aspirin on sFLT1 expression and release in CTBs suggesting that the aspirin effect may be mediated via inhibition of COX1. The study increases our understanding of the mechanisms regulating sFlt1 expression and provides a plausible explanation for the effect of aspirin to prevent preeclampsia.
authors: Department of Obstetrics and Gynecology, Iowa City, IA, USA.
authors: C
authors: C
authors: Li
authors: Division of Nephrology, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, USA.
authors: N S
authors: NS
authors: Raikwar
authors: Department of Obstetrics and Gynecology, Iowa City, IA, USA.
authors: M K
authors: MK
authors: Santillan
authors: Department of Obstetrics and Gynecology, Iowa City, IA, USA.
authors: D A
authors: DA
authors: Santillan
authors: Department of Obstetrics and Gynecology, Iowa City, IA, USA; Division of Nephrology, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, USA; Department of Veterans Affairs Medical Center, Iowa City, IA, USA. Electronic address: christie-thomas@uiowa.edu.
authors: C P
authors: CP
authors: Thomas
mesh_terms: D000328:Adult; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology*; D019556:COS Cells; D000068579:Celecoxib / Q000494:pharmacology; D015687:Cell Hypoxia; D002460:Cell Line; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D051545:Cyclooxygenase 1 / Q000737:chemistry / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006801:Humans; D011225:Pre-Eclampsia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D011720:Pyrazoles / Q000494:pharmacology; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D012995:Solubility; D014327:Trophoblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D011720:Pyrazoles; D011994:Recombinant Proteins; C115461:SC 560; D051545:Cyclooxygenase 1; C496511:PTGS1 protein, human; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1; D000068579:Celecoxib; D001241:Aspirin
keywords: Angiogenesis; Cytotoxicity; Gene expression; Placenta; Preeclampsia
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