The molecular basis of myocardial cell death in the ischernia-reperfused heart still remains to be clarified. Apoptosis signal-regulating kinase I (ASK I) is a mitogen-activated protein kinase kinase kinase that plays an important role in stress-induced apoptosis. We studied ASKl(-/-) mice to examine the role of ASKl in ischemia-reperfusion injury. In the wild-type heart, ischemia-reperfusion resulted in necrotic injury, whereas infarct size was drastically reduced in the ASKl(-/-) heart. The necrotic injury was not accompanied with any evidence of apoptosis such as an increase in TUNEL-positive cells, DNA fragmentation or the activation of caspase-3. ASKl(-/-) cardiomyocytes were more resistant to H2O2- or Ca2+-induced apoptotic and non-apoptotic cell death compared with wild-type cells. These data suggest that ASKl is involved in necrosis as well as apoptosis and that ASKl-dependent necrosis is likely to contribute to myocardial cell death in the ischemia-reperfused heart. (c) 2005 Elsevier Inc. All rights reserved.