Affiliation:
1. From the Departments of Medicine (D.C., I.J., L.B., A.P.B., B.N.-G., J.K., A.L., P.A.) and Physiology (T.H.H.), New York Medical College, Valhalla, NY.
Abstract
Cell death has been questioned as a mechanism of ventricular failure. In this report, we tested the hypothesis that apoptotic death of myocytes, endothelial cells, and fibroblasts is implicated in the development of the dilated myopathy induced by ventricular pacing. Accumulation of reactive oxygen products such as nitrotyrosine, potentiation of the oxidative stress response by p66
shc
expression, formation of p53 fragments, release of cytochrome
c
, and caspase activation were examined to establish whether these events were coupled with apoptotic cell death in the paced dog heart. Myocyte, endothelial cell, and fibroblast apoptosis was detected before indices of severe impairment of cardiac function became apparent. Cell death increased with the duration of pacing, and myocyte death exceeded endothelial cell and fibroblast death throughout. Nitrotyrosine formation and p66
shc
levels progressively increased with pacing and were associated with cell apoptosis. Similarly, p50 (ΔN) fragments augmented paralleling the degree of cell death in the failing heart. Moreover, cytochrome
c
release and activation of caspase-9 and -3 increased from 1 to 4 weeks of pacing. In conclusion, cardiac cell death precedes ventricular decompensation and correlates with the time-dependent deterioration of function in this model. Oxidative stress may be critical for activation of apoptosis in the overloaded heart.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Cardiology and Cardiovascular Medicine,Physiology
Cited by
340 articles.
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