title: Effects of levosimendan on mitochondrial function in patients with septic shock: a randomized trial.
abstract: Mitochondrial dysfunction is key feature of septic shock and contributes to the development of sepsis related organ dysfunction. It is characterized by a variable reduction of the respiratory chain (RC) activities, altered mitochondrial morphology and reactive oxygen species production. Recent data have reported the efficacy of levosimendan, a calcium sensitizer, in improving heart performance and organ perfusion in critically ill patients. Moreover, it has been demonstrated that Levosimendan has antioxidant properties. Nevertheless, the effects of levosimendan on mitochondrial function are not fully elucidated. The objective of this study was therefore to evaluate the effect of levosimendan on mitochondria performance. Five mitochondrial parameters were screened: the redox status; the amount of scavenging enzymes; the activities of the RC complexes; the mitochondrial content; the steady state levels of the RC subunits; the mitochondrial biogenesis. Our results show that patients treated with levosimendan had a significant reduction of glutathionylated proteins and an increase in the amount of the antioxidant enzyme MnSOD, underlining its antioxidant properties. The activities of the RC complexes I, II and III were unchanged in the mitochondria of patients treated with levosimendan compared to controls whereas the mitochondrial content was significantly higher in levosimendan vs. control patients. Finally, evaluation of mitochondrial biogenesis did not show any significant difference in the two groups, although an overall increase in the amount of the RC subunits was observed in the levosimendan group. In conclusion, our study demonstrated that in septic shock patients, Levosimendan exerts antioxidant action by increasing antioxidant defense and lowering oxidative damage.
authors.affiliation: Unit of Molecular Medicine for Neuromuscular and Neurodegenerative Diseases, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Torraco
authors.affiliation: Unit of Molecular Medicine for Neuromuscular and Neurodegenerative Diseases, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Rosalba
authors.initials: R
authors.lastname: Carrozzo
authors.affiliation: Unit of Molecular Medicine for Neuromuscular and Neurodegenerative Diseases, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Fiorella
authors.initials: F
authors.lastname: Piemonte
authors.affiliation: Laboratory of Metabolomics and Proteomics, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Pastore
authors.affiliation: Unit of Molecular Medicine for Neuromuscular and Neurodegenerative Diseases, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Tozzi
authors.affiliation: Unit of Molecular Medicine for Neuromuscular and Neurodegenerative Diseases, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Verrigni
authors.affiliation: Emergency Department 2, University of Rome, "La Sapienza", Rome, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Assenza
authors.affiliation: Department of Cardiovascular, Respiratory, Nephrological, Anesthesiological and Geriatric Sciences, University of Rome, "La Sapienza", Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Orecchioni
authors.affiliation: Department of Cardiovascular, Respiratory, Nephrological, Anesthesiological and Geriatric Sciences, University of Rome, "La Sapienza", Italy.
authors.forename: Annalia
authors.initials: A
authors.lastname: D'Egidio
authors.affiliation: Department of Cardiovascular, Respiratory, Nephrological, Anesthesiological and Geriatric Sciences, University of Rome, "La Sapienza", Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Marraffa
authors.affiliation: Department of Anesthesia and Intensive Care, Università Vita-Salute San Raffaele, Milano, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Landoni
authors.affiliation: Unit of Molecular Medicine for Neuromuscular and Neurodegenerative Diseases, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Bertini
authors.affiliation: Department of Cardiovascular, Respiratory, Nephrological, Anesthesiological and Geriatric Sciences, University of Rome, "La Sapienza", Italy. Electronic address: andrea.morelli@uniroma1.it.
authors.forename: Andrea
authors.initials: A
authors.lastname: Morelli
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D042967:Electron Transport Complex I / Q000378:metabolism*; D005260:Female; D006439:Hemodynamics; D006801:Humans; D006835:Hydrazones / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000201:enzymology / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D011724:Pyridazines / Q000008:administration & dosage*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012772:Shock, Septic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000077464:Simendan; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism
chemical_list: D006835:Hydrazones; D011724:Pyridazines; D017382:Reactive Oxygen Species; D000077464:Simendan; D013482:Superoxide Dismutase; D042967:Electron Transport Complex I
keywords: Glutathione; Levosimendan; Mitochondria; Oxidative stress; Sepsis