Mild hypothermia pretreatment protects against liver ischemia reperfusion injury via the PI3K/AKT/FOXO3a pathway

Abstract

Mild hypothermia is known to protect against ischemia and reperfusion (IR) injury. The exact mechanisms of the protection are not fully understood. Forkhead box O3 (FOXO3a) has been defined as a critical mediator in cellular processes, including oxidative stress, apoptosis, inflammation, cell death and DNA repair; however, the protection function in mild hypothermia has not been reported previously. The current study was designed to investigate the function of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/FOXO3a pathway in pretreatment with mild hypothermia during IR injury. Additionally, PI3K/AKT/FOXO3a signaling was inhibited using Ly294002 and the effect on the protective function of mild hypothermia pretreatment was evaluated. Furthermore, the apoptotic and inflammatory response induced by the IR injury was evaluated. Liver IR injury induced a significant increase in the level of apoptosis and inflammatory responses. However, pretreatment with mild hypothermia increased phospho (p)-AKT and p-FOXO3a following IR injury, and significantly reduced apoptosis and inflammatory cytokines release. However, inhibiting p-AKT and p-FOXO3a using Ly294002 suppressed the liver protection produced by mild hypothermia. In conclusion, these findings indicated that mild hypothermia pretreatment exhibited liver protective effects against IR injury associated with suppressing inflammatory cytokine release and apoptosis via the PI3K/AKT/FOXO3a pathway.

Hesperidin ameliorates liver ischemia/reperfusion injury via activation of the Akt pathway

“…The PI3K/Akt pathway is a protective pathway in liver I/R injury (11,12,32,44,49). Akt is considered to be a potential therapeutic target for liver I/R (12).…”

Moderate Hypothermia Effectively Alleviates Acetaminophen-Induced Liver Injury With Prolonged Action Beyond Cooling

“…In contrast, even though apoptosis does not largely evoke cell death in AILI, the stark difference in the mode of hepatoprotection during the rewarming phase may encourage the versatile use of TH for different causes of liver injuries, other than APAP. 55 Lastly, we went further to explore its impact on the key functions of hepatocytes, namely its drug-metabolizing ability and its clearance capacity. With a subtle temperature downshift in moderate hypothermia, signature phase I (CYP3A4) and phase II (GSTP1) drug-metabolizing enzymes deviated largely in their behavior, with greater perturbation seen with GSTP1 in injured hepatocytes (Figure 7).…”

“…In contrast, even though apoptosis does not largely evoke cell death in AILI, the stark difference in the mode of hepatoprotection during the rewarming phase may encourage the versatile use of TH for different causes of liver injuries, other than APAP. 55 …”

The Role of O-GlcNAcylation for Protection against Ischemia-Reperfusion Injury

“…A preconditioning stimulus seems to activate NF-κB, and pharmacological inhibition of NF-κB abolishes the cardioprotective effect of preconditioning [74,75]. The finding is ambiguous because protection in some models, including models of non-cardiac IPC, is associated with depression of NF-κB [76,77,78].…”