RECOMBINANT ADENOVIRUS-MEDIATED CARDIAC GENE-TRANSFER OF SUPEROXIDE-DISMUTASE AND CATALASE ATTENUATES POSTISCHEMIC CONTRACTILE DYSFUNCTION

Background-Coronary revascularization entails obligatory myocardial is chemia followed by reperfusion with occasional resultant postischemic contractile dysfunction, a state associated with significant morbidity and mortality. This injury is attributed in part to oxygen free radic als and has been partially ameliorated with exogenous antioxidants, a strategy limited by agent instability, low titer, and inadequate cardi omyocyte uptake. Cardiac gene transfer with antioxidant encoding vecto rs may significantly enhance intracellular free radical scavenger acti vity. Methods and Results-C57/BL6 neonatal mice (age, 2 days n=131) un derwent intrapericardial delivery of recombinant adenoviruses encoding superoxide dismutase (SOD) and catalase (Cat) (n=76) or beta-galactos idase (LacZ) as a control (n=55). After 3 days, hearts were explanted, and SOD and Cat transgene expression was detected by Western blot ana lysis. Spectrophotometric enzyme assays demonstrated enhanced SOD acti vity 1.6-fold (P<0.0001) and Cat 3.6-fold (P<0.00001) in experimental versus LacZ hearts. Isolated perfused hearts were subjected to 5 minut es of warm ischemia, and at 5, 10, and 15 minutes after initiation of reperfusion, LacZ controls lost 24%, 33%, and 41% of peak systolic api cobasal force, respectively, whereas experimental hearts lost 5%, 12%, and 20% (P<0.001, each time point). In controls, rate of force genera tion diminished 8%, 17%, and 35%; in experimental hearts, it increased 1% at 5 minutes and decreased 5% and 15% at 10 and 15 minutes (p<0.01 , p<0.05, p<0.05). LacZ hearts exhibited dysfunction similar to hearts from uninjected animals (P=NS, each time point). Conclusions-Adenovir us-mediated cardiac gene transfer and expression of SOD and Cat augmen t antioxidant enzyme activity and minimize contractile dysfunction aft er ischemic reperfusion in the isolated perfused neonatal mouse heart.