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Protection by selective mTORC2 inhibition of Zymosan-induced hypotension and systemic inflammation mediated via

Zainab Sabrie1, Meryem Temiz-Resitoglu1, Taskin Kalkan1

  • 1Department of Pharmacology, Faculty of Pharmacy, Mersin University, Mersin, Turkey.

Prostaglandins & Other Lipid Mediators
|October 26, 2024
PubMed

Insights

This study reveals that targeting the mTORC2 pathway with JR-AB2-011 can reverse hypotension and inflammation in a non-septic shock rat model. This highlights mTORC2

Area of Science:

  • Physiology
  • Immunology
  • Pharmacology

Background:

  • Non-septic shock causes organ dysfunction, with mTORC1's anti-inflammatory role known, but mTORC2's involvement is unclear.
  • The IκB kinase (IKKα)/inhibitor κB (IκB-α)/nuclear factor-ĸB (NF-κB) pathway is implicated in inflammatory responses.

Purpose of the Study:

  • To investigate the role of mTORC2 in Zymosan (ZYM)-induced non-septic shock.
  • To evaluate the effects of the novel mTORC2 selective inhibitor JR-AB2-011 on this model.
  • To elucidate the involvement of the IKKα/IκB-α/NF-κB pathway.

Main Methods:

  • A Zymosan (ZYM)-induced non-septic shock rat model was established.
  • Rats were treated with saline, DMSO, ZYM, and/or JR-AB2-011.
  • Hemodynamic parameters (MAP, HR) and protein/mediator levels (rictor, Akt, IκB-α, IKKα, NF-κB p65, iNOS, nitrotyrosine, COX-2, TNF-α, IL-1β, PGE2) were assessed.

Main Results:

  • JR-AB2-011 administration reversed ZYM-induced reductions in mean arterial pressure (MAP) and increases in heart rate (HR).
  • JR-AB2-011 inhibited the enhanced expression and/or phosphorylation of key inflammatory proteins and mediators.
  • These effects were associated with modulation of the IKKα/IκB-α/NF-κB pathway.

Conclusions:

  • mTORC2 plays a significant role in ZYM-induced non-septic shock, contributing to hypotension and systemic inflammation.
  • The mTORC2 inhibitor JR-AB2-011 demonstrates therapeutic potential for non-septic shock.
  • The IKKα/IκB-α/NF-κB pathway is a key mediator of mTORC2's effects in this model.
Keywords:
HypotensionInflammationRatZymosanmTORnon-septic shock

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