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Propofol post-conditioning alleviates hepatic ischaemia reperfusion injury via BRG1-mediated Nrf2/HO-1 transcriptional activation in human and mice.
- Source :
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Journal of cellular and molecular medicine [J Cell Mol Med] 2017 Dec; Vol. 21 (12), pp. 3693-3704. Date of Electronic Publication: 2017 Jul 27. - Publication Year :
- 2017
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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.<br /> (© 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)
- Subjects :
- Adolescent
Adult
Aged
Animals
Cell Line
DNA Helicases metabolism
Drug Repositioning
Female
Gene Expression Regulation
Heme Oxygenase-1 metabolism
Hepatitis metabolism
Hepatitis pathology
Hepatitis surgery
Hepatocytes drug effects
Hepatocytes metabolism
Hepatocytes pathology
Humans
Hypnotics and Sedatives therapeutic use
Liver metabolism
Liver pathology
Liver surgery
Liver Neoplasms metabolism
Liver Neoplasms pathology
Liver Neoplasms surgery
Male
Mice
Mice, Inbred C57BL
Middle Aged
NF-E2-Related Factor 2 metabolism
Nuclear Proteins metabolism
Oxidative Stress drug effects
Prospective Studies
Reperfusion Injury genetics
Reperfusion Injury metabolism
Reperfusion Injury pathology
Transcription Factors metabolism
Antioxidants therapeutic use
DNA Helicases genetics
Heme Oxygenase-1 genetics
Liver Transplantation methods
NF-E2-Related Factor 2 genetics
Nuclear Proteins genetics
Propofol therapeutic use
Reperfusion Injury prevention & control
Transcription Factors genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1582-4934
- Volume :
- 21
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Journal of cellular and molecular medicine
- Publication Type :
- Academic Journal
- Accession number :
- 28749008
- Full Text :
- https://doi.org/10.1111/jcmm.13279