Remifentanil up‐regulates HIF1α expression to ameliorate hepatic ischaemia/reperfusion injury via the ZEB1/LIF axis

Abstract

Ischaemia/reperfusion (I/R)‐induced hepatic injury is regarded as a main reason of hepatic failure after transplantation or lobectomy. The current study aimed to investigate how the opioid analgesic remifentanil treatment affects I/R‐induced hepatic injury and explore the possible mechanisms related to HIF1α. Initially, an I/R‐induced hepatic injury animal model was established in C57BL/6 mice, and an in vitro hypoxia‐reoxygenation model was constructed in NCTC‐1469 cells, followed by remifentanil treatment and HIF1α silencing treatment. The levels of blood glucose, lipids, alanine transaminase (ALT) and aspartate transaminase (AST) in mouse serum were measured using automatic chemistry analyser, while the viability and apoptosis of cells were detected using CCK8 assay and flow cytometry. Our results revealed that mice with I/R‐induced hepatic injury showed higher serum levels of blood glucose, lipids, ALT and AST and leukaemia inhibitory factor (LIF) expression, and lower HIF1α and ZEB1 expression (P < .05), which were reversed after remifentanil treatment (P < .05). Besides, HIF1α silencing increased the serum levels of blood glucose, lipids, ALT and AST (P < .05). Furthermore, hypoxia‐induced NCTC‐1469 cells exhibited decreased HIF1α and ZEB1 expression, reduced cell viability, as well as increased LIF expression and cell apoptosis (P < .05), which were reversed by remifentanil treatment (P < .05). Moreover, HIF1α silencing down‐regulated ZEB1 expression, decreased cell viability, and increased cell apoptosis (P < .05). ZEB1 was identified to bind to the promoter region of LIF and inhibit its expression. In summary, remifentanil protects against hepatic I/R injury through HIF1α and downstream effectors.

Histone deacetylase 6 deficiency protects the liver against ischemia/reperfusion injury by activating PI3K/AKT/mTOR signaling

“…Specifically, the restraint of Bax by AKT suppresses apoptosis by reducing caspase 3 activity 45,46 . A recent study found that activated phosphorylated AKT dramatically mitigates IRI in the liver 47 . In the present study, we found that the PI3K/AKT/mTOR pathway was significantly suppressed after hepatic IRI but could be activated by HDAC6 deletion.…”

“…45,46 A recent study found that activated phosphorylated AKT dramatically mitigates IRI in the liver. 47 In the present study, we found that the PI3K/ AKT/mTOR pathway was significantly suppressed after hepatic IRI but could be activated by HDAC6 deletion. Moreover, HDAC6 overexpression produced the opposite trend.…”

Corrigendum

“…In Rongsheng Zhou et al, 1 incorrect images were used in Figure 1B , Figure 2D , Figure 3M and Figure 5I . The correct figures are shown below.…”