Endothelin-1 (ET-1) is a potent survival factor against myocardial cell apoptosis. This anti-apoptotic effect of ET-I is mediated in part through calcineurin[NFATc-dependent induction of bcl-2 expression. Since it has been reported that peroxisome proliferator-activated receptor-gamma (PPARgamma) interacts with NFATc, we investigated the effects of PPARgamma ligands on anti-apoptotic effects of ET-I in cardiac myocytes. In primary cardiac myocytes from neonatal rats, administration of PPARgamma activators (15-deoxy-Delta(12,14)-prostaglandin J(2), and troglitazone) attenuated the anti-apoptotic effects of ET-1. These activators abolished the ET-I-stimulated increase in bcl-2 expression and in binding of cardiac NFATc to the bcl-2 NFAT site. These findings demonstrate that activators of PPARgamma perturb the anti-apoptotic effects of ET-I in cardiac myocytes and that this perturbation is, in part, based on functional transcriptional cross-talk between NFATc and PPARgamma. (C) 2004 Elsevier Inc. All rights reserved.