title: Pre- or post-ischemic bilirubin ditaurate treatment reduces oxidative tissue damage and improves cardiac function.
abstract: BACKGROUND
  Unconjugated bilirubin (UCB), an endogenous antioxidant, may protect the heart against ischemia-reperfusion (I-R) injury. However, the 'cardioprotective' potential of bilirubin therapy remains unclear. We tested whether pre- or post-ischemic treatment of ex vivo perfused hearts with bilirubin ditaurate (BRT) improves post-ischemic functional outcomes and myocardial oxidative damage.
  
  
  METHODS
  Isolated Langendorff perfused hearts (male, Wistar rats) were treated with 50 μM BRT for 30 min before (Pre) or after (Post) 30 min of zero-flow ischemia. Functional outcomes were monitored, with myocardial damage estimated from creatine kinase efflux, infarct size, and left ventricular lipid/protein oxidation assessed by measuring malondialdehyde and protein carbonyls. Ischemia induced contractile dysfunction and cellular injury, with both BRT treatments improving I-R outcomes.
  
  
  RESULTS
  Final post-ischemic recoveries for left ventricular diastolic/developed pressures were significantly enhanced in treated groups: end-diastolic pressure (Control, 78±14, Pre, 51±15*, Post, 51±13 mm Hg*); left ventricular developed pressure, (LVDP; Control 44±15, Pre, 71±19*, Post, 84±13 mm Hg*). Myocardial injury/infarction (MI) was also significantly reduced with BRT treatment: post-ischemic creatine kinase efflux (Control, 1.24±0.41, Pre, 0.86±0.31*, Post, 0.51±0.29 U/g/mL*; infarct size, Control, 67±17, Pre, 39±15*, Post, 22±11%*). These changes were accompanied by significantly reduced malondialdehyde and protein carbonyl content in Pre and Post treated hearts (*P<0.05 vs. Control).
  
  
  CONCLUSIONS
  These data collectively reveal significant cardioprotection upon BRT treatment, with post-treatment being particularly effective. Significant reductions in infarct size and lipid and protein oxidation indicate a mechanism related to protection from oxidative damage and indicate the potential utility of this molecule as a post-MI treatment.
authors.affiliation: Heart Foundation Research Centre, Griffith Health Institute, Griffith University, Gold Coast, Australia.
authors.forename: Bhavisha
authors.initials: B
authors.lastname: Bakrania
authors.affiliation: Heart Foundation Research Centre, Griffith Health Institute, Griffith University, Gold Coast, Australia.
authors.forename: Eugene F
authors.initials: EF
authors.lastname: Du Toit
authors.affiliation: Heart Foundation Research Centre, Griffith Health Institute, Griffith University, Gold Coast, Australia; Department of Nutritional Science, University of Vienna, Vienna, Austria.
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Wagner
authors.affiliation: Heart Foundation Research Centre, Griffith Health Institute, Griffith University, Gold Coast, Australia.
authors.forename: John P
authors.initials: JP
authors.lastname: Headrick
authors.affiliation: Heart Foundation Research Centre, Griffith Health Institute, Griffith University, Gold Coast, Australia. Electronic address: a.bulmer@griffith.edu.au.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Bulmer
mesh_terms: D000818:Animals; D001663:Bilirubin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D003326:Coronary Circulation; D003402:Creatine Kinase / Q000378:metabolism; D004195:Disease Models, Animal; D005878:Gilbert Disease / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D006325:Heart Atria / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006352:Heart Ventricles / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D017208:Rats, Wistar; D013654:Taurine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D016896:Treatment Outcome; D016277:Ventricular Function, Left / Q000187:drug effects* / Q000502:physiology
chemical_list: D013654:Taurine; C054146:bilirubin ditaurine; D003402:Creatine Kinase; D001663:Bilirubin
keywords: Antioxidant; Gilbert's syndrome; Heme oxygenase; Myocardial ischemia–reperfusion; Oxidative stress