title: Myocardial creatine levels do not influence response to acute oxidative stress in isolated perfused heart.
abstract: BACKGROUND
  Multiple studies suggest creatine mediates anti-oxidant activity in addition to its established role in cellular energy metabolism. The functional significance for the heart has yet to be established, but antioxidant activity could contribute to the cardioprotective effect of creatine in ischaemia/reperfusion injury.
  
  
  OBJECTIVE
  To determine whether intracellular creatine levels influence responses to acute reactive oxygen species (ROS) exposure in the intact beating heart. We hypothesised that mice with elevated creatine due to over-expression of the creatine transporter (CrT-OE) would be relatively protected, while mice with creatine-deficiency (GAMT KO) would fare worse.
  
  
  RESULTS
  CrT-OE mice were pre-selected for creatine levels 20-100% above wild-type using in vivo (1)H-MRS. Hearts were perfused in isovolumic Langendorff mode and cardiac function monitored throughout. After 20 min equilibration, hearts were perfused with either H2O2 0.5 µM (30 min), or the anti-neoplastic drug doxorubicin 15 µM (100 min). Protein carbonylation, creatine kinase isoenzyme activities and phospho-PKCδ expression were quantified in perfused hearts as markers of oxidative damage and apoptotic signalling. Wild-type hearts responded to ROS challenge with a profound decline in contractile function that was ameliorated by co-administration of catalase or dexrazoxane as positive controls. In contrast, the functional deterioration in CrT-OE and GAMT KO hearts was indistinguishable from wild-type controls, as was the extent of oxidative damage and apoptosis. Exogenous creatine supplementation also failed to protect hearts from doxorubicin-induced dysfunction.
  
  
  CONCLUSIONS
  Intracellular creatine levels do not influence the response to acute ROS challenge in the intact beating heart, arguing against creatine exerting (patho-)physiologically relevant anti-oxidant activity.
authors.affiliation: Division of Cardiovascular Medicine, Radcliffe Department of Medicine and British Heart Foundation Centre of Research Excellence, University of Oxford, Oxford, United Kingdom.
authors.forename: Dunja
authors.initials: D
authors.lastname: Aksentijević
authors.affiliation: Division of Cardiovascular Medicine, Radcliffe Department of Medicine and British Heart Foundation Centre of Research Excellence, University of Oxford, Oxford, United Kingdom.
authors.forename: Sevasti
authors.initials: S
authors.lastname: Zervou
authors.affiliation: Division of Cardiovascular Medicine, Radcliffe Department of Medicine and British Heart Foundation Centre of Research Excellence, University of Oxford, Oxford, United Kingdom.
authors.forename: Kiterie M E
authors.initials: KM
authors.lastname: Faller
authors.affiliation: Division of Cardiovascular Medicine, Radcliffe Department of Medicine and British Heart Foundation Centre of Research Excellence, University of Oxford, Oxford, United Kingdom.
authors.forename: Debra J
authors.initials: DJ
authors.lastname: McAndrew
authors.affiliation: Division of Cardiovascular Medicine, Radcliffe Department of Medicine and British Heart Foundation Centre of Research Excellence, University of Oxford, Oxford, United Kingdom.
authors.forename: Jurgen E
authors.initials: JE
authors.lastname: Schneider
authors.affiliation: Division of Cardiovascular Medicine, Radcliffe Department of Medicine and British Heart Foundation Centre of Research Excellence, University of Oxford, Oxford, United Kingdom.
authors.forename: Stefan
authors.initials: S
authors.lastname: Neubauer
authors.affiliation: Division of Cardiovascular Medicine, Radcliffe Department of Medicine and British Heart Foundation Centre of Research Excellence, University of Oxford, Oxford, United Kingdom.
authors.forename: Craig A
authors.initials: CA
authors.lastname: Lygate
mesh_terms: D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000378:metabolism; D003401:Creatine / Q000378:metabolism*; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism*; D018384:Oxidative Stress; D010865:Pilot Projects; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D015415:Biomarkers; D017382:Reactive Oxygen Species; D003401:Creatine