Previous study demonstrated that overexpression of ZAK induced cardiac hypertrophy and elevated ANF expression. ZAK also causes the apoptosis of hepatoma cell line. A critical role of apoptosis was suggested as a pathogenic mechanism of cardiac diseases. In this study, we investigate whether overexpression of ZAK could enhance cardiomyocyte death and alter contraction function. The data revealed that expression of wild type, continuous active, but not dominative negative ZAK show apoptosis analyzed by TUNEL assay, and promoted caspase 3 activity by western blotting in H9C2 cells. Downregulation of phospho-Bad and phospho-PLB, and calcineurin-induced nuclear translocation of NF-ATc1 were also shown. ZAK-overpressed H9C2 cells treated with CsA, a calcineurin inhibitor, demonstrated the inhibition of ZAK-induced apoptosis. None of wild type, continuous active and dominative negative expression of ZAK in AngII-treated H9C2 affects apoptotic signaling activity. These results demonstrate ZAK induced cardiomyocyte apoptosis via calcineurin signaling pathway without AngII signaling involvement, and affected cardiac relaxation-contraction coupling by decreasing phospho-PLB.
