Loss of Akt activity increases circulating soluble endoglin release in preeclampsia:identification of inter-dependency between Akt-1 and heme oxygenase-1

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Cudmore, Melissa J. ; Ahmad, Shakil ; Sissaoui, Samir ; Ramma, Wenda ; Ma, Bin ; Fujisawa, Takeshi ; Al-Ani, Bahjat ; Wang, Keqing ; Cai, Meng ; Crispi, Fatima ; Hewett, Peter W. ; Gratacós, Eduard ; Egginton, Stuart ; Ahmed, Asif (2012)
  • Publisher: Oxford University Press
  • Journal: European Heart Journal, volume 33, issue 9, pages 1,150-1,158 (issn: 0195-668X, eissn: 1522-9645)
  • Related identifiers: pmc: PMC3341632, doi: 10.1093/eurheartj/ehr065
  • Subject: /dk/atira/pure/subjectarea/asjc/2700/2705 | Basic Science | Endothelium | Cardiology and Cardiovascular Medicine | HO-1 | Preeclampsia | Soluble endoglin | PI3K/Akt

Aims 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. <br/>Methods and 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. <br/>Conclusion 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.
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