title: Loss of Akt activity increases circulating soluble endoglin release in preeclampsia: identification of inter-dependency between Akt-1 and heme oxygenase-1.
abstract: OBJECTIVE
  Endothelial dysfunction is a hallmark of preeclampsia. Desensitization of the phosphoinositide 3-kinase (PI3K)/Akt pathway underlies endothelial dysfunction and haeme oxygenase-1 (HO-1) is decreased in preeclampsia. To identify therapeutic targets, we sought to assess whether these two regulators act to suppress soluble endoglin (sEng), an antagonist of transforming growth factor-β (TGF-β) signalling, which is known to be elevated in preeclampsia.
  
  
  RESULTS
  Vascular endothelial growth factor-A (VEGF-A), fibroblast growth factor (FGF-2), angiopoietin-1 (Ang-1), and insulin, which all activate the PI3K/Akt pathway, inhibited the release of sEng from endothelial cells. Inhibition of the PI3K/Akt pathway, by overexpression of phosphatase and tensin homolog (PTEN) or a dominant-negative isoform of Akt (Akt(dn)) induced sEng release from endothelial cells and prevented the inhibitory effect of VEGF-A. Conversely, overexpression of a constitutively active Akt (Akt(myr)) inhibited PTEN and cytokine-induced sEng release. Systemic delivery of Akt(myr) to mice significantly reduced circulating sEng, whereas Akt(dn) promoted sEng release. Phosphorylation of Akt was reduced in preeclamptic placenta and this correlated with the elevated level of circulating sEng. Knock-down of Akt using siRNA prevented HO-1-mediated inhibition of sEng release and reduced HO-1 expression. Furthermore, HO-1 null mice have reduced phosphorylated Akt in their organs and overexpression of Akt(myr) failed to suppress the elevated levels of sEng detected in HO-1 null mice, indicating that HO-1 is required for the Akt-mediated inhibition of sEng.
  
  
  CONCLUSIONS
  The loss of PI3K/Akt and/or HO-1 activity promotes sEng release and positive manipulation of these pathways offers a strategy to circumvent endothelial dysfunction.
authors.affiliation: University / BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, College of Medicine and Veterinary Medicine, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Cudmore
authors.forename: Shakil
authors.initials: S
authors.lastname: Ahmad
authors.forename: Samir
authors.initials: S
authors.lastname: Sissaoui
authors.forename: Wenda
authors.initials: W
authors.lastname: Ramma
authors.forename: Bin
authors.initials: B
authors.lastname: Ma
authors.forename: Takeshi
authors.initials: T
authors.lastname: Fujisawa
authors.forename: Bahjat
authors.initials: B
authors.lastname: Al-Ani
authors.forename: Keqing
authors.initials: K
authors.lastname: Wang
authors.forename: Meng
authors.initials: M
authors.lastname: Cai
authors.forename: Fatima
authors.initials: F
authors.lastname: Crispi
authors.forename: Peter W
authors.initials: PW
authors.lastname: Hewett
authors.forename: Eduard
authors.initials: E
authors.lastname: Gratacós
authors.forename: Stuart
authors.initials: S
authors.lastname: Egginton
authors.forename: Asif
authors.initials: A
authors.lastname: Ahmed
mesh_terms: D042683:Angiopoietin-1 / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D000071063:Endoglin; D004730:Endothelium, Vascular / Q000378:metabolism; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011225:Pre-Eclampsia / Q000201:enzymology*; D011247:Pregnancy; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014471:Umbilical Veins / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D042683:Angiopoietin-1; D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; D007328:Insulin; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D051547:Heme Oxygenase-1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase