title: Ouabain inhibits placental sFlt1 production by repressing HSP27-dependent HIF-1α pathway.
abstract: Up-regulation of placental soluble fms-like tyrosine kinase 1 (sFlt1) contributes to the pathogenesis of preeclampsia. To evaluate novel upstream pathways that regulate placental sFlt1 production, we screened a library of natural compounds (n=502) in human placental cell lines. Here, we report 3 compounds in the cardiac glycoside family, ouabain, gitoxigenin, and digitoxin, that inhibit placental sFlt1 production at nanomolar concentrations in vitro. We further characterized ouabain and demonstrated that it inhibits sFlt1 mRNA and protein expression in human placental cytotrophoblasts and explant cultures in a dose- and time-dependent manner. Ouabain down-regulated sFlt1 production by inhibiting hypoxia-inducible factor 1 (HIF-1α) protein expression in the placenta. Furthermore, we found that phosphorylation of heat-shock protein 27 (HSP27) was necessary for ouabain to inhibit HIF-1α translation. In a rat model of pregnancy-induced hypertension, ouabain reduced mean arterial pressure and enhanced placental HSP27 phosphorylation without any adverse effects on pups. Further studies are needed to explore the usefulness of targeting HIF-1α/HSP27 pathway in preeclampsia.
authors: Maternal Fetal Medicine/Obstetrics and Gynecology and Harvard Medical School, Boston, Massachusetts, USA; srana1@bidmc.harvard.edu.
authors: Sarosh
authors: S
authors: Rana
authors: Center for Vascular Biology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA; Harvard Medical School, Boston, Massachusetts, USA; Howard Hughes Medical Institute, Boston, Massachusetts, USA; and.
authors: Augustine
authors: A
authors: Rajakumar
authors: Center for Vascular Biology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA;
authors: Carl
authors: C
authors: Geahchan
authors: Maternal Fetal Medicine/Obstetrics and Gynecology and Harvard Medical School, Boston, Massachusetts, USA;
authors: Saira
authors: S
authors: Salahuddin
authors: Center for Vascular Biology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA;
authors: Ana Sofia
authors: AS
authors: Cerdeira
authors: Center for Vascular Biology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA; Harvard Medical School, Boston, Massachusetts, USA; Howard Hughes Medical Institute, Boston, Massachusetts, USA; and.
authors: Suzanne D
authors: SD
authors: Burke
authors: Department of Physiology, University of Mississippi Medical Center, Jackson, Mississippi, USA.
authors: Eric M
authors: EM
authors: George
authors: Department of Physiology, University of Mississippi Medical Center, Jackson, Mississippi, USA.
authors: Joey P
authors: JP
authors: Granger
authors: Maternal Fetal Medicine/Obstetrics and Gynecology and Center for Vascular Biology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA; Harvard Medical School, Boston, Massachusetts, USA; Howard Hughes Medical Institute, Boston, Massachusetts, USA; and.
authors: S Ananth
authors: SA
authors: Karumanchi
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002298:Cardenolides / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D002478:Cells, Cultured; D004074:Digitoxin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D046110:Hypertension, Pregnancy-Induced / Q000188:drug therapy / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D010042:Ouabain / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D010766:Phosphorylation; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D002298:Cardenolides; D002316:Cardiotonic Agents; C497442:HIF1A protein, human; D055551:HSP27 Heat-Shock Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D010042:Ouabain; D004074:Digitoxin; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1; C007846:gitoxigenin
keywords: angiogenesis; hypertension; preeclampsia