The p38 mitogen-activated protein kinase (p38) is activated in the heart during ischemia-reperfusion. However, it is not clear whether the activation of p38 is the protective response or the kinase mediates the cellular damage by ischemia-reperfusion. We examined the role of p38alpha in ischemia-reperfusion injury by studying p38alpha(+/-) mice. The p38alpha protein level in the p38alpha(+/-) heart was 50+/-8.7% compared with that in the p38alpha(+/+) heart. Upon reperfusion following ischemia for 25 min, p38alpha activity was transiently increased. The maximum level of p38 activity in p38alpha(+/-) was 60+/-10.5% compared with that in p38alpha(+/+). In the p38alpha(+/+) heart, 25 min ischemia and 2 h reperfusion resulted in necrotic injury (37.1+/-2.7% of the area at risk), whereas infarct size was drastically reduced to 7.2+/-0.7% in the P38alpha(+/-) heart. These suggested that p38alpha plays a pivotal role in the signal transduction pathway mediating myocardial cell death caused by ischemia-reperfusion. (C) 2003 Elsevier Science (USA). All rights reserved.