Aldosterone induces extracellular signal-regulated kinase (ERK)-dependent cardiac remodeling. Fenofibrate improves cardiac remodeling in adult rat cardiomyocytes (ARVM) partly via inhibition of aldosterone-induced ERK1/2 phosphorylation and inhibition of matrix metalloproteinases. We sought to determine whether aldosterone caused apoptosis in cultured adult cardiomyocytes (ARVM) and whether fenofibrate ameliorated the apoptosis. Aldosterone (1mM) induced apoptosis by increasing terminal uridine deoxynucleotide transferase dUTP nick end labeling (TUNEL) positive nuclei in ARVM. Spironolactone (100nM), an aldosterone receptor antagonist but not RU486, a glucocorticoid receptor, inhibited aldosterone-mediated apoptosis indicating that the mineralocorticoid receptor (MR) plays a role. SP600125 (3µM) - a selective inhibitor of c-Jun N-terminal kinase (JNK), inhibited aldosterone-induced apoptosis in ARVM. Although aldosterone increased the expression of both stress activated protein kinases, pretreatment with fenofibrate (10µM) decreased aldosterone-mediated apoptosis by inhibiting only JNK phosphorylation and the aldosterone-induced increases in Bax, p53 and cleaved caspase-3 and decreases in Bcl-2 protein expression in ARVM. In vivo studies demonstrated that chronic fenofibrate (100mg/kg body weight/day) inhibited myocardial Bax and increased Bcl-2 expression in aldosterone-induced cardiac hypertrophy. Similarly eplerenone, a selective MR inhibitor, used in chronic pressure overload ascending aortic constriction inhibited myocardial Bax expression but had no effect on Bcl-2 expression. Thus, in conclusion, involvement of JNK MAPK-dependant mitochondrial death pathway mediates ARVM aldosterone-induced apoptosis and is inhibited by fenofibrate, a PPAR ligand. Fenofibrate mediates beneficial effects in cardiac remodeling by inhibiting programmed cell death and the stress-activated kinases.