beta-adrenergic pathway induces apoptosis through calcineurin activation in cardiac myocytes

Apoptosis of cardiac myocytes is one of the causes of heart failure. Here w e examine the mechanism by which the activation of beta -adrenergic recepto r induces cardiomyocyte apoptosis. Terminal deoxynucleotide transferase-med iated dUTP nick end labeling and DNA ladder analyses revealed that isoprote renol (Iso) induced the apoptosis of cardiac myocytes of neonatal rats thro ugh an increase in intracellular Ca2+ levels. The Iso-induced cardiomyocyte apoptosis was strongly inhibited by the L-type Ca2+ channel antagonist nif edipine and by the calcineurin inhibitors cyclosporin A and FK506. Iso redu ced the phosphorylation levels of the proapoptotic Bcl-2 family protein Bad and induced cytochrome c release from mitochondria to the cytosol through calcineurin activation. Infusion of Iso increased calcineurin activity by s imilar to3-fold in the hearts of wild-type mice but not in the hearts of tr ansgenic mice that overexpress dominant negative mutants of calcineurin. Te rminal deoxynucleotide transferase-mediated dUTP nick end labeling analysis revealed that infusion of Iso induced apoptosis of cardiac myocytes and th at the number of apoptotic cardiomyocytes was significantly less in the hea rts of the transgenic mice compared with the wild-type mice. These results suggest that calcineurin plays a critical role in Iso-induced apoptosis of cardiac myocytes, possibly through dephosphorylating Bad.