Oxidative stress-mediated cardiac cell death is a major determinant of ventricular dysfunction and failure in dog dilated cardiomyopathy

Cell death has been questioned as a mechanism of ventricular failure. In th is report, we tested the hypothesis that apoptotic death of myocytes, endot helial cells, and fibroblasts is implicated in the development of the dilat ed myopathy induced by ventricular pacing. Accumulation of reactive oxygen products such as nitrotyrosine, potentiation of the oxidative stress respon se by p66(shc) expression, formation of p53 fragments, release of cytochrom e c, and caspase activation were examined to establish whether these events were coupled with apoptotic cell death in the paced dog heart. Myocyte, en dothelial cell, and fibroblast apoptosis was detected before indices of sev ere impairment of cardiac function became apparent. Cell death increased wi th the duration of pacing, and myocyte death exceeded endothelial cell and fibroblast death throughout. Nitrotyrosine formation and p66(shc) levels pr ogressively increased with pacing and were associated with cell apoptosis. Similarly, p50 (DeltaN) fragments augmented paralleling the degree of cell death in the failing heart. Moreover, cytochrome c release and activation o f caspase-9 and -3 increased from 1 to 4 weeks of pacing. In conclusion, ca rdiac cell death precedes ventricular decompensation and correlates with th e time-dependent deterioration of function in this model. Oxidative stress may be critical for activation of apoptosis in the overloaded heart.