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Inorganic polyphosphate elicits pro‐inflammatory responses through activation of the mammalian target of rapamycin complexes 1 and 2 in vascular endothelial cells
Author(s) -
Hassanian S. M.,
Dinarvand P.,
Smith S. A.,
Rezaie A. R.
Publication year - 2015
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.12899
Subject(s) - mtorc1 , pi3k/akt/mtor pathway , mtorc2 , phosphorylation , signal transduction , gene knockdown , microbiology and biotechnology , protein kinase b , cancer research , p70 s6 kinase 1 , biology , mechanistic target of rapamycin , rptor , chemistry , cell culture , genetics
Summary Background Inorganic polyphosphate (polyP) elicits pro‐inflammatory signaling responses in endothelial cells through interaction with two receptors, RAGE and P2Y 1 . It is known that polyP activates mTOR signaling in breast cancer cells. Objectives 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 si RNA knockdown of specific signaling molecules. Results PolyP effectively induced phosphorylation of mTOR complex 1 ( mTORC 1) substrate, p70S6K, in endothelial cells by an AKT ‐dependent but ERK ‐independent mechanism. The si RNA knockdown of both RAGE and P2Y 1 or specific inhibitors of the PI 3K/ PLC / PKC /Ca 2+ signaling axis inhibited polyP‐mediated p70S6K phosphorylation. Moreover, either rapamycin or si RNA knockdown of raptor ( mTORC 1‐specific component) abrogated polyP‐mediated phosphorylation of p70S6K. By contrast, the si RNA knockdown of rictor ( mTOR complex 2‐specific component) but not raptor eliminated the barrier‐disruptive effect of polyP. Specific NF ‐ κ B inhibitors abrogated polyP‐mediated phosphorylation of p70S6K and rapamycin suppressed polyP‐induced activation of NF ‐ κ B. 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 P2Y 1 , activates both the mTORC 1 and mTORC 2 signaling network. Both the pro‐inflammatory and mTOR signaling functions of polyP are linked.