Protection by selective mTORC2 inhibition of Zymosan-induced hypotension and systemic inflammation mediated via IKKα/IκB-α/NF-κB activation

Abstract

Non-septic shock is a serious condition leading to multiple organ dysfunction. Although targeting the mammalian target of the rapamycin complex 1 (mTORC1) signaling pathway exerts potent anti-inflammatory activity, little is known about mTORC2’s contribution to non-septic shock. Thus, our research aims to investigate mTORC2's contribution and associated changes of IκB kinase (IKKα)/inhibitor κB (IκB-α)/nuclear factor-ĸB (NF-κB) pathway on Zymosan (ZYM)-induced non-septic rat model using the novel mTORC2 selective inhibitor JR-AB2–011. Rats were given saline (4 ml/kg), dimethylsulfoxide (DMSO) (4 ml/kg), ZYM (500 mg/kg), and (or) JR-AB2–011 (1 mg/kg). Mean arterial pressure (MAP) and heart rate (HR) of rats were recorded. JR-AB2–011 reversed both ZYM-induced reduction in MAP and increase in HR. Protein expression and/or phosphorylation of rictor, protein kinase B (Akt), IκB-α, IKKα, NF-κB p65, inducible nitric oxide synthase (iNOS), nitrotyrosine, cyclooxygenase 2 (COX-2), tumor necrosis factor (TNF)-α, interleukin (IL)-1β, besides prostaglandin (PG) E₂ levels were measured. The enhanced expression of the proteins mentioned above has been inhibited by JR-AB2–011. These data suggest mTORC2’s promising role in ZYM-induced hypotension and systemic inflammation mediated via IKKα/IκB-α/NF-κB pathway.