Propofol post‐conditioning alleviates hepatic ischaemia reperfusion injury via BRG1‐mediated Nrf2/HO‐1 transcriptional activation in human and mice

Mian Ge,Chaojin Chen,Qianqian Zhu,Weifeng Yao,Yi Jin,Jun Cai,Dongdong Yuan,Huixin Chen,Ziqing Hei

doi:10.1111/jcmm.13279

Mian Ge, Chaojin Chen + Show 7 more

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https://doi.org/10.1111/jcmm.13279

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Abstract

To explore the effects of propofol post‐conditioning (PPC) on hepatic ischaemia/reperfusion injury (HIRI) and the potential mechanisms that might be involved in the interaction of Brahma‐related gene1(BRG1) and Nuclear‐related factor 2(Nrf2). Patients were randomized into PPC(n = 16) and non‐PPC(NPC)( n = 21) groups. Propofol(2 mg/kg) was infused within 10 min. of the onset of liver reperfusion during liver transplantation in the PPC group. Liver function tests, as well as Brg1, Nrf2, Heme oxygenase‐1(HO‐1) and NADPH:quinone oxidoreductase1(NQO1) expression levels were evaluated. CMV‐Brg1 mice were designed to investigate the role of Brg1 overexpression during HIRI. Brg1 and Nrf2 siRNA were used to examine the relationship between Brg1 and Nrf2/HO‐1 pathways in propofol‐mediated effects in a human hepatocyte(L02) hypoxia/reoxygenation(H/R) model. In patients, PPC attenuated both donor liver pathological and function injury, and reducing oxidative stress markers, compared to the NPC group, 24 hrs after surgery. PPC increased liver Brg1, Nrf2, HO‐1 and NQO1 expression. In mice, PPC reduced HIRI by decreasing liver oxidative stress and activating Nrf2/HO‐1 pathway, accompanied by up‐regulation of BRG1 expression. BRG1 overexpression activated Nrf2/HO‐1 transcription in CMV‐BRG1 mice during HIRI. In vitro, PPC significantly elevated expression of Nrf2, HO‐1 and NQO1, resulting in a reduction of cell DCFH‐DA and 8‐isoprostane levels and decreased lactate dehydrogenase levels, leading to an overall increase in cell viability. Moreover, the protective effects of propofol were partially abrogated in Nrf2‐knock‐down or BRG1‐knock‐down hepatocytes. Nrf2‐knock‐down drastically reduced protein expression of HO‐1 and NQO1, while Brg1‐knock‐down decreased HO‐1 expression. Propofol post‐conditioning alleviates HIRI through BRG1‐mediated Nrf2/HO‐1 transcriptional activation.

Highlights

The primary cause of early allograft injury following orthotopic liver transplantation (OLT) or liver resection is hepatic ischaemia/reperfusion injury (HIRI), and is associated with allograft dysfunction and patient mortality [1]
In comparison with the NPC group, the expressions of BRG1, nuclear-related factor2 (Nrf2), heme oxygenase 1 (HO-1) and NADPH:quinone oxidoreductase 1 (NQO1) in the PPC group were significantly higher (P < 0.05). These results demonstrate that propofol post-conditioning promoted the expressions of BRG1, Nrf2, HO-1 and NQO1 after reperfusion, which may be related to the protective effects of propofol
We confirmed that post-conditioning with propofol alleviated allograft injury in OLT patients and HIRI in mice

Summary

Introduction

The primary cause of early allograft injury following orthotopic liver transplantation (OLT) or liver resection is HIRI, and is associated with allograft dysfunction and patient mortality [1]. Studies have suggested that enhancing antioxidant capacity may be a potential therapeutic approach to reducing the incidence of HIRI. Repeated ischaemic conditioning and several pharmacological agents have been shown to enhance hepatic antioxidative abilities and alleviate HIRI [3, 8, 9]. This approach is often challenging due to the inherent complexities associated with surgery

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