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

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.

• Authors: Mian Ge, Huixin Chen, Qianqian Zhu, Jun Cai, Chaojin Chen, Dongdong Yuan, Yi Jin, Weifeng Yao, Ziqing Hei
• Journal: Journal of cellular and molecular medicine (J Cell Mol Med) Vol. 21 Issue 12 Pg. 3693-3704 (Dec 2017) ISSN: 1582-4934 [Electronic] England
• PMID: 28749008 (Publication Type: Journal Article, Randomized Controlled Trial)
• Copyright: © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Chemical References

• Antioxidants
• Hypnotics and Sedatives
• NF-E2-Related Factor 2
• NFE2L2 protein, human
• Nuclear Proteins
• Transcription Factors
• HMOX1 protein, human
• Heme Oxygenase-1
• SMARCA4 protein, human
• DNA Helicases
• Propofol

Topics

• Adolescent
• Adult
• Aged
• Animals
• Antioxidants (therapeutic use)
• Cell Line
• DNA Helicases (genetics, metabolism)
• Drug Repositioning
• Female
• Gene Expression Regulation
• Heme Oxygenase-1 (genetics, metabolism)
• Hepatitis (metabolism, pathology, surgery)
• Hepatocytes (drug effects, metabolism, pathology)
• Humans
• Hypnotics and Sedatives (therapeutic use)
• Liver (metabolism, pathology, surgery)
• Liver Neoplasms (metabolism, pathology, surgery)
• Liver Transplantation (methods)
• Male
• Mice
• Mice, Inbred C57BL
• Middle Aged
• NF-E2-Related Factor 2 (genetics, metabolism)
• Nuclear Proteins (genetics, metabolism)
• Oxidative Stress (drug effects)
• Propofol (therapeutic use)
• Prospective Studies
• Reperfusion Injury (genetics, metabolism, pathology, prevention & control)
• Transcription Factors (genetics, metabolism)