The transcription factor STAT1 plays a role in promoting apoptotic cell death, whereas the related STAT3 transcription factor protects cardiac myocytes from ischemia/reperfusion (I/R) injury or oxidative stress. Cytokines belonging to the IL-6 family activate the JAK-STAT3 pathway, but also activate other cytoprotective pathways such as the MAPK-ERK or the PI3-AKT pathway. It is therefore unclear whether STAT3 is the only cytoprotective mediator against oxidative stress-induced cell death. Overexpression of STAT3 in primary neonatal rat ventricular myocytes (NRVM) protects against I/R-induced cell death. Moreover, a dominant negative STAT3 adenovirus (Ad ST3-DN) enhanced apoptotic cell death (81.2 +/- 6.9%) compared to control infected NRVM (46.0 +/- 3.1%) following I/R. Depletion of STAT3 sensitized cells to apoptotic cell death following oxidative stress. These results provide direct evidence for the role of STAT3 as a cytoprotective transcription factor in cells exposed to oxidative stress. (C) 2009 Elsevier Inc. All rights reserved.