Abstract 337: cAbl Tyrosine Kinase Increases Catalase Activity in the Catalase-Dysregulated Newborn Rabbit Heart
Introduction: Pediatric patients undergoing corrective cardiothoracic surgery numbered in the tens of thousands annually and therefore it is necessary that pre- and post-operative strategies be employed to limit ischemia-reperfusion (IR) injury. We have found differences in the way the newborn (versus the adult) heart responds to IR injury. In the adult, catalase activity increases appropriately with increasing levels of hydrogen peroxide (H2O2), conferring cardioprotection. This effect however does not occur in the newborn.
Materials and Methods: Hypoxia studies were carried out using primary cardiomyocytes from adult (>8 weeks) and newborn rats. Ischemia-reperfusion (IR) studies were performed using newborn (4-5 days) rabbits. Isolated rat cardiomyocytes were exposed to 1 hour of hypoxia (95%N2,5%CO2). Immunoprecipitation and western blot analysis were done for phosphorylated and total catalase and c-Abl. In addition, catalase activity was determined spectrophotometrically by measuring the decomposition of H2O2. Newborn rabbit hearts were perfused using Langendorff method with ischemia and reperfusion periods lasting 30 and 60 minutes, respectively. DPH (200µM), a cAbl activator was injected directly into the newborn right ventricle (RV) two minutes before the reperfusion period.
Results: Following hypoxia, the ratio of phosphorylated to total catalase and c-Abl in isolated newborn rat myocytes did not increase and were significantly lower (1.92- and 6.21-fold, respectively; p<0.05) than their adult counterparts. Interestingly, when DPH was administered one hour prior to hypoxia, not only was catalase activity significantly increased 6.28-fold (p<0.01) but phosphorylation levels were also altered. Finally, direct injection of DPH into the RV of Langendorff-perfused newborn rabbit hearts caused a significant improvement in percent recovery of developed pressure (from 49.53±5.42% to 125.5±15.5%) after IR, a key indicator of cardiac function. Catalase activity in these same hearts increased 2.92-fold.
Conclusion: In the newborn, decreased phosphorylation of catalase by c-Abl potentially mediates IR-induced dysfunction. Activation of c-Abl may be a strategy to prevent ischemic injury associated with surgical procedures.
- © 2013 by American Heart Association, Inc.