Heme oxygenase-1-derived bilirubin ameliorates postischemic myocardial dysfunction

Bilirubin is a potent antioxidant generated intracellularly during the degr adation of heme by the enzyme heme oxygenase. The purpose of this study was to determine the role of increased cardiac bilirubin in protection against postischemic myocardial dysfunction. Rat hearts were isolated and perfused according to the Langendorff technique to evaluate the recovery of myocard ial function after 30 min of global ischemia and 60 min of reperfusion. We found that upregulation of the inducible isoform of heme oxygenase (HO-1) b y treatment of animals with hemin 24 h before ischemia ameliorated myocardi al function and reduced infarct size (tetrazolium staining) on reperfusion of isolated hearts. Tin protoporphyrin IX, an inhibitor of heme oxygenase a ctivity, completely abolished the improved postischemic myocardial performa nce observed after hemin-mediated HO-1 induction. Likewise, cardiac tissue injury was exacerbated by treatment with tin protoporphyrin IX. Increased c ardiac HO-1 expression and heme oxygenase activity were associated with enh anced tissue bilirubin content and an increased rate of bilirubin release i nto the perfusion buffer. Furthermore, exogenously administered bilirubin a t concentrations as low as 100 nanomolar significantly restored myocardial function and minimized both infarct size and mitochondrial damage on reperf usion. Our data provide strong evidence for a primary role of HO-1-derived bilirubin in cardioprotection against reperfusion injury.