Stress-induced mitogen-activated protein (MAP) kinases have been implicated in various forms of cardiovascular diseases. Ischemia/reperfusion potentiates activation of p38 MAP kinase (p38MAPK) leading to the activation of its downstream target MAPKAP kinase 2 (MK2). While p38MAPK has been shown to induce pro-apoptotic signal, whether MK2 also generates death signal is not known. To determine if MK2 triggers death signal, the hearts of MK2-/- knockout mice and genetically matched wild-type mice were subjected to 30 min ischemia followed by 2 h of reperfusion via Langendorff mode. The results indicated that the hearts of MK2-/- mice were resistant to myocardial ischemic reperfusion injury as evidenced by enhance recovery of post-ischemic ventricular performance, reduced myocardial infarct size and diminished number of apoptotic cardiomyocytes. We conclude that MK2, similar to p38MAPK, is involved in transmitting the death signal to the ischemic myocardium.