Inhibition of p38 mitogen-activated protein kinase decreases cardiomyocyteapoptosis and improves cardiac function after myocardial ischemia and reperfusion

Background-Activation of p38 mitogen-activated protein kinase (MAPK) plays an important role in apoptotic cell death. The role of p38 MAPK in myocardi al injury caused by ischemia/reperfusion, an extreme stress to the heart, i s unknown. Methods and Results-Studies were performed with isolated, Langendorff-perfu sed rabbit hearts. Ischemia alone caused a moderate but transient increase in p38 MAPK activity (3.5-fold increase, P<0.05 versus basal). Ischemia fol lowed by reperfusion further activated p38 MAPK, and the maximal level of a ctivation (6.3-fold, P<0.01) was reached 10 minutes after reperfusion. Admi nistration of SE 203580, a p38 MAPK inhibitor, decreased myocardial apoptos is (14.7+/-3.2% versus 30.6+/-3.5% in vehicle, P<0.01) and improved postisc hemic cardiac function. The cardioprotective effects of SE 203580 were-clos ely related to its inhibition of p38 MAPK. Administering SE 203580 before i schemia and during reperfusion completely inhibited p38 MAPK activation and exerted the most cardioprotective effects. Tn contrast, administering SE 2 03580 10 minutes after reperfusion (a time point when maximal MAPK activati on had already been achieved) failed to convey significant cardioprotection . Moreover, inhibition of p38 MARK attenuated myocardial necrosis after a p rolonged reperfusion. Conclusions-These results demonstrate that p38 MAPK plays a pivotal role in the signal transduction pathway mediating postischemic myocardial apoptosi s and that inhibiting p38 MAPK may attenuate reperfusion injury.