Inhibition of p38 reduces myocardial infarction injury in the mouse but not pig after ischemia-reperfusion.
The MAPK family member p38 is activated in the heart after ischemia-reperfusion (I/R) injury. However, the cardioprotective vs. proapoptotic effects associated with p38 activation in the heart after I/R injury remain 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 vs. 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 after I/R at baseline or with the selective p38 inhibitor SB-239063. Infusion of SB-239063 5 min before ischemia in the mouse prevented ischemia-induced p38 activation, resulting in a 25% reduction of infarct size compared with vehicle-treated animals (27.9 +/- 2.9% vs. 37.5 +/- 2.7%). In the pig, SB-239063 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 I/R 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.
Kaiser
Robert A
RA
Dept. of Pediatrics, Cincinnati Children's Hospital Medical Center, Univ. of Cincinnati, 3333 Burnet Ave., Cincinnati, OH 45229, USA.
Lyons
Jefferson M
JM
Duffy
Jodie Y
JY
Wagner
Connie J
CJ
McLean
Kelly M
KM
O'Neill
Timothy P
TP
Pearl
Jeffrey M
JM
Molkentin
Jeffery D
JD
D000818:Animals; D007093:Imidazoles / Q000008:administration & dosage*; D051379:Mice; D009203:Myocardial Infarction / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology*; D011743:Pyrimidines / Q000008:administration & dosage*; D015427:Reperfusion Injury / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology*; D015203:Reproducibility of Results; D012720:Severity of Illness Index; D013045:Species Specificity; D013552:Swine; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*
D007093:Imidazoles; D011743:Pyrimidines; D048051:p38 Mitogen-Activated Protein Kinases; C406525:SB 239063