title: Inorganic polyphosphate elicits pro-inflammatory responses through activation of the mammalian target of rapamycin complexes 1 and 2 in vascular endothelial cells.
abstract: BACKGROUND
  Inorganic polyphosphate (polyP) elicits pro-inflammatory signaling responses in endothelial cells through interaction with two receptors, RAGE and P2Y1 . It is known that polyP activates mTOR signaling in breast cancer cells.
  
  
  OBJECTIVE
  The objective of this study is to understand the mechanism of the polyP-mediated signaling pathway in endothelial cells and to determine whether polyP exerts its pro-inflammatory effect through activation of mTOR.
  
  
  METHODS
  mTOR activation by polyP or platelet releasates in cellular and animal models was monitored in the absence and presence of pharmacological inhibitors and/or siRNA knockdown of specific signaling molecules.
  
  
  RESULTS
  PolyP effectively induced phosphorylation of mTOR complex 1 (mTORC1) substrate, p70S6K, in endothelial cells by an AKT-dependent but ERK-independent mechanism. The siRNA knockdown of both RAGE and P2Y1 or specific inhibitors of the PI3K/PLC/PKC/Ca(2+) signaling axis inhibited polyP-mediated p70S6K phosphorylation. Moreover, either rapamycin or siRNA knockdown of raptor (mTORC1-specific component) abrogated polyP-mediated phosphorylation of p70S6K. By contrast, the siRNA knockdown of rictor (mTOR complex 2-specific component) but not raptor eliminated the barrier-disruptive effect of polyP. Specific NF-κB inhibitors abrogated polyP-mediated phosphorylation of p70S6K and rapamycin suppressed polyP-induced activation of NF-κB. Finally, specific inhibitors of the mTOR signaling network eliminated polyP-mediated vascular leakage and leukocyte recruitment in animal models.
  
  
  CONCLUSIONS
  PolyP, through interaction with RAGE and P2Y1 , activates both the mTORC1 and mTORC2 signaling network. Both the pro-inflammatory and mTOR signaling functions of polyP are linked.
authors.affiliation: Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, Saint Louis, MO, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Hassanian
authors.forename: P
authors.initials: P
authors.lastname: Dinarvand
authors.forename: S A
authors.initials: SA
authors.lastname: Smith
authors.forename: A R
authors.initials: AR
authors.lastname: Rezaie
mesh_terms: D000818:Animals; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D007249:Inflammation / Q000139:chemically induced*; D007287:Inorganic Chemicals / Q000494:pharmacology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D011122:Polyphosphates / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D007287:Inorganic Chemicals; D046912:Multiprotein Complexes; D016328:NF-kappa B; D011122:Polyphosphates; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases
keywords: NF-kappa B; TOR serine-threonine kinases; blood platelets; capillary permeability; inflammation; polyphosphates