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1 Pediatrics, Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA
2 Surgery, Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA
3 Procter and Gamble Pharmaceuticals, Mason, OH, USA
* To whom correspondence should be addressed. E-mail: jeff.molkentin{at}cchmc.org.
The mitogen-activated protein kinase (MAPK) family member p38 is activated in the heart following ischemia-reperfusion injury (IR). However, the cardio-protective versus pro-apoptotic effects associated with p38 activation in the heart following IR injury remains unresolved. Another issue to consider is that the majority of past studies have employed the rodent as a model for assessing p38's role in cardiac injury versus protection, while the potential regulatory role in a large animal model is even more uncertain. Here we performed a parallel study in the mouse and pig to directly compare the extent of cardiac injury following IR at baseline or with the selective p38 inhibitor SB239063. Infusion of SB239063 five minutes prior to ischemia in the mouse prevented ischemia-induced p38 activation, resulting in a 25% reduction of infarct size compared to vehicle-treated animals (27.9±2.9 % vs. 37.5±2.7 %). In the pig, SB239063 similarly inhibited myocardial p38 activation, but there was no corresponding effect on the degree of infarction injury (43.6±4.0 % vs. 41.4±4.3 %). These data suggest a difference in myocardial responsiveness to IR between the small animal mouse model and the large animal pig model, such that p38 activation in the mouse contributes to acute cellular injury and death, while the same activation in pig has no causative effect on these parameters.
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