title: Propofol but not sevoflurane prevents mitochondrial dysfunction and oxidative stress by limiting HIF-1α activation in hepatic ischemia/reperfusion injury.
abstract: Mitochondrial dysfunction, reactive oxygen species (ROS) production and oxidative stress during reperfusion are determinant in hepatic ischemia/reperfusion (I/R) injury but may be impacted by different anesthetic agents. Thus, we aimed at comparing the effects of inhaled sevoflurane or intravenous propofol anesthesia on liver mitochondria in a rodent model of hepatic I/R injury. To this, male Wistar rats underwent I/R surgery using sevoflurane or propofol. In the I/R model, propofol limited the raise in serum aminotransferase levels as compared to sevoflurane. Mitochondrial oxygen uptake, respiratory activity, membrane potential and proton leak were altered in I/R; however, this impairment was significantly prevented by propofol but not sevoflurane. In addition, differently from sevoflurane, propofol limited hepatic I/R-induced mitochondria H2O2 production rate, free radical leak and hydroxynonenal-protein adducts levels. The I/R group anesthetized with propofol also showed a better recovery of hepatic ATP homeostasis and conserved integrity of mitochondrial PTP. Moreover, hypoxia-inducible factor 1 alpha (HIF-1α) expression was limited in such group. By using a cell model of desferoxamine-dependent HIF activation, we demonstrated that propofol was able to inhibit apoptosis and mitochondrial depolarization associated to HIF-1α action. In conclusion, hepatic I/R injury induces mitochondrial dysfunction that is not prevented by inhaled sevoflurane. On the contrary, propofol reduces liver damage and mitochondrial dysfunction by preserving respiratory activity, membrane potential and energy homeostasis, and limiting free radicals production as well as PTP opening. These hepatoprotective effects may involve the inhibition of HIF-1α.
authors.affiliation: C.U.R.E. University Centre for Liver Disease Research and Treatment, Institute of Internal Medicine, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy. Electronic address: francesco.bellanti@unifg.it.
authors.forename: Francesco
authors.initials: F
authors.lastname: Bellanti
authors.affiliation: Department of Anesthesia and Intensive Care, University of Foggia, Foggia, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Mirabella
authors.affiliation: C.U.R.E. University Centre for Liver Disease Research and Treatment, Institute of Internal Medicine, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
authors.forename: Domenica
authors.initials: D
authors.lastname: Mitarotonda
authors.affiliation: C.U.R.E. University Centre for Liver Disease Research and Treatment, Institute of Internal Medicine, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Blonda
authors.affiliation: C.U.R.E. University Centre for Liver Disease Research and Treatment, Institute of Internal Medicine, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Tamborra
authors.affiliation: Department of Anesthesia and Intensive Care, University of Foggia, Foggia, Italy.
authors.forename: Gilda
authors.initials: G
authors.lastname: Cinnella
authors.affiliation: Department of General Surgery, University of Foggia, Foggia, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Fersini
authors.affiliation: Department of General Surgery, University of Foggia, Foggia, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Ambrosi
authors.affiliation: Department of Anesthesia and Intensive Care, University of Foggia, Foggia, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Dambrosio
authors.affiliation: C.U.R.E. University Centre for Liver Disease Research and Treatment, Institute of Internal Medicine, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Vendemiale
authors.affiliation: C.U.R.E. University Centre for Liver Disease Research and Treatment, Institute of Internal Medicine, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
authors.forename: Gaetano
authors.initials: G
authors.lastname: Serviddio
mesh_terms: D000777:Anesthetics / Q000008:administration & dosage; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D005609:Free Radicals / Q000633:toxicity; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics*; D008099:Liver / Q000187:drug effects / Q000293:injuries / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008738:Methyl Ethers / Q000008:administration & dosage; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D010456:Peptides, Cyclic / Q000008:administration & dosage; D015742:Propofol / Q000008:administration & dosage*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000077149:Sevoflurane
chemical_list: D000777:Anesthetics; D005609:Free Radicals; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008738:Methyl Ethers; D010456:Peptides, Cyclic; D017382:Reactive Oxygen Species; C410730:desferriexochelin 772SM; D000077149:Sevoflurane; D006861:Hydrogen Peroxide; D015742:Propofol
keywords: Anesthetics; Apoptosis; Ischemia/reperfusion; Liver mitochondria