Ischemia-induced STAT-1 expression and activation play a critical role in cardiomyocyte apoptosis

We show here that exposure of cardiac cells to simulated ischemia results i n apoptosis and is accompanied by phosphorylation and increased expression and transcriptional activity of STAT-1, Similarly, interferon-gamma, which is known to induce STAT-1 activation, also induced apoptosis in cardiac cel ls, STAT-1-transfected cells were more susceptible to ischemia-induced cell death than cells transfected with a control plasmid lacking the STAT-1 cod ing sequence. Furthermore, an antisense STAT-1 vector reduced both ischemia -and overexpressed STAT-1-induced cell death in cardiac cells. Both STAT-1 overexpression and interferon-gamma treatment or exposure to ischemia activ ated the promoter of the pro-apoptotic caspase-1 gene in cardiomyocytes. Fi nally, ischemia/reperfusion also induced STAT-1 activation and caspase-1 pr ocessing in ventricular myocytes in the intact heart er vivo. Immunofluores cent staining demonstrated an increase in STAT-1-positive staining in cardi omyocytes in response to ischemia/reperfusion that co-localized with termin al deoxynucleotidyl transferase dVTP nick end-labeling-positive apoptotic c ells. These results suggest that STAT-1 plays a critical role in the regula tion of ischemia/reperfusion-induced apoptosis in cardiac cells, acting at least in part via a caspase-1 activation-dependent pathway.