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. 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 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/Ca2+ 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.
CITATION STYLE
Hassanian, S. M., Dinarvand, P., Smith, S. A., & Rezaie, A. R. (2015). Inorganic polyphosphate elicits pro-inflammatory responses through activation of the mammalian target of rapamycin complexes 1 and 2 in vascular endothelial cells. Journal of Thrombosis and Haemostasis, 13(5), 860–871. https://doi.org/10.1111/jth.12899
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