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Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
09:18

Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death

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The effects of mTOR-Akt interactions on anti-apoptotic signaling in vascular endothelial cells

Olivier Dormond1, Joren C Madsen, David M Briscoe

  • 1Transplant Research Center, Division of Nephrology, Department of Medicine, Children's Hospital, Boston, Massachusetts 02115, USA.

The Journal of Biological Chemistry
|June 8, 2007
PubMed

Insights

The mechanistic target of rapamycin (mTOR) pathway regulates Akt activation in endothelial cells, suppressing pro-survival signals and promoting apoptosis when inhibited.

Area of Science:

  • Endothelial cell biology
  • Molecular signaling pathways
  • Cellular apoptosis

Background:

  • The mechanistic target of rapamycin (mTOR) pathway is known to activate the protein kinase Akt in various cell types.
  • The specific association between mTOR and Akt in vascular endothelial cells remains largely uncharacterized.
  • The functional importance of mTOR/Akt signaling within the endothelium has not been elucidated.

Purpose of the Study:

  • To investigate the role of mTOR in regulating Akt activation within endothelial cells.
  • To determine the functional consequences of mTOR/Akt signaling inhibition on endothelial cell survival.

Main Methods:

  • Endothelial cells were treated with the mTOR inhibitor rapamycin.
  • Akt phosphorylation and activity were assessed using its substrate, glycogen synthase kinase-3.
  • Experiments involved endothelial cells transfected with a rapamycin-resistant mTOR construct.
  • The impact of rapamycin on growth factor- and insulin-induced Akt phosphorylation was examined.
  • Phosphorylation and inactivation of Akt substrates Foxo1 and Foxo3a were analyzed.
  • Endothelial cell apoptosis was quantified following serum withdrawal or stimulation with vascular endothelial growth factor (VEGF) or tumor necrosis factor (TNF).

Main Results:

  • Rapamycin treatment decreased Akt phosphorylation and activity in endothelial cells.
  • This effect was dependent on mTOR, as rapamycin did not inhibit Akt in cells with resistant mTOR.
  • Rapamycin blocked Akt phosphorylation induced by VEGF, TNF, and insulin.
  • Rapamycin inhibited VEGF- and Akt-inducible phosphorylation of pro-apoptotic factors Foxo1 and Foxo3a.
  • Inhibition of Akt activity by rapamycin increased endothelial cell apoptosis under various conditions.

Conclusions:

  • mTOR plays a critical role in regulating Akt phosphorylation and activation in vascular endothelial cells.
  • Inhibition of mTOR in endothelial cells suppresses Akt-mediated pro-survival signals.
  • These findings highlight the significance of the mTOR/Akt pathway in maintaining endothelial cell viability.

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