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(Circulation. 1999;99:1685-1691.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Inhibition of p38 Mitogen-Activated Protein Kinase Decreases Cardiomyocyte Apoptosis and Improves Cardiac Function After Myocardial Ischemia and Reperfusion
From the Division of Emergency Medicine (X.L.M., F.G., B.L.L., T.A.C.), Thomas Jefferson University, Philadelphia, and the Departments of Bone and Cartilage (S.K., J.C.L.), Experimental Toxicology (C.S.L.), and Cardiovascular Pharmacology (C.W., G.Z.F., T.-L.Y.), SmithKline Beecham Pharmaceuticals, King of Prussia, Pa.
Correspondence to Xin L. Ma, MD, PhD, Division of Emergency Medicine, Jefferson Medical College, 1020 Sansom St, Philadelphia, PA 19107. E-mail ma1{at}jeflin.tju.edu
Background—Activation of p38 mitogen-activated protein kinase (MAPK) plays an important role in apoptotic cell death. The role of p38 MAPK in myocardial injury caused by ischemia/reperfusion, an extreme stress to the heart, is unknown.
Methods and Results—Studies were performed with isolated, Langendorff-perfused rabbit hearts. Ischemia alone caused a moderate but transient increase in p38 MAPK activity (3.5-fold increase, P<0.05 versus basal). Ischemia followed by reperfusion further activated p38 MAPK, and the maximal level of activation (6.3-fold, P<0.01) was reached 10 minutes after reperfusion. Administration of SB 203580, a p38 MAPK inhibitor, decreased myocardial apoptosis (14.7±3.2% versus 30.6±3.5% in vehicle, P<0.01) and improved postischemic cardiac function. The cardioprotective effects of SB 203580 were closely related to its inhibition of p38 MAPK. Administering SB 203580 before ischemia and during reperfusion completely inhibited p38 MAPK activation and exerted the most cardioprotective effects. In contrast, administering SB 203580 10 minutes after reperfusion (a time point when maximal MAPK activation had already been achieved) failed to convey significant cardioprotection. Moreover, inhibition of p38 MAPK attenuated myocardial necrosis after a prolonged reperfusion.
Conclusions—These results demonstrate that p38 MAPK plays a pivotal role in the signal transduction pathway mediating postischemic myocardial apoptosis and that inhibiting p38 MAPK may attenuate reperfusion injury.
Key Words: reperfusion • signal transduction • apoptosis • contractality • myocardial infarction
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