Astrid Kleber1, Christian G Ruf2, Alexander Wolf3, Tobias Fink4, Michael Glas5, Beate Wolf6, Thomas Volk7, Michael Abend8, Alexander M Mathes9. 1. Department of Anaesthesiology, Intensive Care and Pain Therapy, Saarland University Medical Center, Homburg (Saar), Germany. Electronic address: astrid.kleber@uks.eu. 2. Department of Urology, Bundeswehrkrankenhaus Koblenz, Germany. Electronic address: christianruf@bundeswehr.org. 3. Department of Anaesthesiology, Intensive Care and Pain Therapy, Saarland University Medical Center, Homburg (Saar), Germany. Electronic address: alexander.wolf@uks.eu. 4. Department of Anaesthesiology, Intensive Care and Pain Therapy, Saarland University Medical Center, Homburg (Saar), Germany. Electronic address: tobias.fink@uks.eu. 5. Department of Anaesthesiology, Intensive Care and Pain Therapy, Saarland University Medical Center, Homburg (Saar), Germany. 6. Department of Anaesthesiology, Intensive Care and Pain Therapy, Saarland University Medical Center, Homburg (Saar), Germany. Electronic address: beate.wolf@uks.eu. 7. Department of Anaesthesiology, Intensive Care and Pain Therapy, Saarland University Medical Center, Homburg (Saar), Germany. Electronic address: thomas.volk@uks.eu. 8. Bundeswehr Institute of Radiobiology, München, Germany. Electronic address: michaelabend@bundeswehr.org. 9. Department of Anaesthesiology, Düsseldorf University Hospital, Germany. Electronic address: alexander.mathes@med.uni-duesseldorf.de.
Abstract
BACKGROUND & AIMS: Melatonin has been demonstrated to reduce liver damage in different models of stress. However, there is only limited information on the impact of this hormone on hepatic gene expression. The aim of this study was, to investigate the influence of melatonin or the melatonergic agonist ramelteon on hepatic gene expression profiles after haemorrhagic shock using a whole genome microarray analysis. METHODS: Male Sprague-Dawley rats (200-300 g, n=4/group) underwent haemorrhagic shock (mean arterial pressure 35±5 mmHg). After 90 min of shock, animals were resuscitated with shed blood and Ringer's and treated with vehicle (5% dimethyl sulfoxide), melatonin or ramelteon (each 1.0 mg/kg intravenously). Sham-operated animals were treated likewise but did not undergo haemorrhage. After 2 h of reperfusion, the liver was harvested, and a whole genome microarray analysis was performed. Functional gene expression profiles were determined using the Panther® classification system; promising candidate genes were evaluated by quantitative polymerase chain reaction (PCR). RESULTS: Microarray and PCR data showed a good correlation (r(2)=0.84). A strong influence of melatonin on receptor mediated signal transduction was revealed using the functional gene expression profile analysis, whereas ramelteon mainly influenced transcription factors. Shock-induced upregulation of three candidate genes with relevant functions for hepatocytes (ppp1r15a, dusp5, rhoB) was significantly reduced by melatonin (p<0.05 vs. shock/vehicle), but not by ramelteon. Two genes previously known as haemorrhage-induced (il1b, s100a8) were transcriptionally repressed by both drugs. CONCLUSIONS: Melatonin and ramelteon appear to induce specific hepatic gene expression profiles after haemorrhagic shock in rats. The observed differences between both substances are likely to be attributable to a distinct mechanism of action in these agents.
BACKGROUND & AIMS:Melatonin has been demonstrated to reduce liver damage in different models of stress. However, there is only limited information on the impact of this hormone on hepatic gene expression. The aim of this study was, to investigate the influence of melatonin or the melatonergic agonist ramelteon on hepatic gene expression profiles after haemorrhagic shock using a whole genome microarray analysis. METHODS: Male Sprague-Dawley rats (200-300 g, n=4/group) underwent haemorrhagic shock (mean arterial pressure 35±5 mmHg). After 90 min of shock, animals were resuscitated with shed blood and Ringer's and treated with vehicle (5% dimethyl sulfoxide), melatonin or ramelteon (each 1.0 mg/kg intravenously). Sham-operated animals were treated likewise but did not undergo haemorrhage. After 2 h of reperfusion, the liver was harvested, and a whole genome microarray analysis was performed. Functional gene expression profiles were determined using the Panther® classification system; promising candidate genes were evaluated by quantitative polymerase chain reaction (PCR). RESULTS: Microarray and PCR data showed a good correlation (r(2)=0.84). A strong influence of melatonin on receptor mediated signal transduction was revealed using the functional gene expression profile analysis, whereas ramelteon mainly influenced transcription factors. Shock-induced upregulation of three candidate genes with relevant functions for hepatocytes (ppp1r15a, dusp5, rhoB) was significantly reduced by melatonin (p<0.05 vs. shock/vehicle), but not by ramelteon. Two genes previously known as haemorrhage-induced (il1b, s100a8) were transcriptionally repressed by both drugs. CONCLUSIONS:Melatonin and ramelteon appear to induce specific hepatic gene expression profiles after haemorrhagic shock in rats. The observed differences between both substances are likely to be attributable to a distinct mechanism of action in these agents.
Authors: Alexander M Mathes; Paul Heymann; Christian Ruf; Ragnar Huhn; Jochen Hinkelbein; Thomas Volk; Tobias Fink Journal: Antioxidants (Basel) Date: 2019-09-18