Circulation Research. 2001
Published online before print July 19, 2001, doi: 10.1161/hh1501.094115
Published online before print July 19, 2001, doi: 10.1161/hh1501.094115
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© 2001 American Heart Association, Inc.
Article |
Oxidative Stress–Mediated Cardiac Cell Death Is a Major Determinant of Ventricular Dysfunction and Failure in Dog Dilated Cardiomyopathy
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.
Correspondence to Piero Anversa, MD, Department of Medicine, Cardiovascular Research Institute, New York Medical College, Vosburgh Pavilion, Room 302A, Valhalla, NY 10595. E-mail piero_anversa{at}nymc.edu
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 p66shc 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 p66shc levels progressively increased with pacing and were associated with cell apoptosis. Similarly, p50 (
N) 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.
Key Words: oxidative stress response • p53 fragments • p66shc • caspases • heart failure
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