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From the Departments of Medicine and Physiology, New York Medical
College, Valhalla, NY; the Department of Medicine, Montefiore Medical Center
and Albert Einstein College of Medicine, New York, NY; and the Departments of
Pathology, Anatomy, and Cell Biology and Institute for Cancer Research and
Molecular Medicine, Jefferson Medical College, Philadelphia, Pa.
Background—Rapid
ventricular pacing in dogs is characterized by a dilated
myopathy in which myocyte cell death by apoptosis may play a
significant role in the impairment of cardiac pump function. However,
the molecular mechanisms implicated in the modulation of programmed
cell death under this setting remain to be identified. Moreover,
questions have been raised on the specificity and sensitivity of the
histochemical detection of DNA strand breaks in nuclei by the terminal
deoxynucleotidyl transferase (TdT)
reaction.
Methods and Results—Changes in the expression of
Bcl-2 and Bax and their transcriptional
regulator, p53, were determined by Western blot analysis in
myocytes isolated from dogs affected by pacing-induced heart failure. A
mobility shift assay for p53 binding activity was also performed. In
addition, apoptosis was measured by confocal microscopy, which
allowed the simultaneous detection of chromatin alterations
and DNA damage. p53 DNA binding activity to the bax
promoter was increased in nuclear extracts from myocytes obtained from
failing hearts, and this response was associated with enhanced
expression of Bax protein, 52%, and attenuation of
Bcl-2, -92%. Immunolabeling of p53 in myocyte nuclei,
measured by confocal microscopy, was 100% higher in cells from paced
hearts. The combination of the TdT assay and confocal microscopy
demonstrated that 20 myocyte nuclei per 106 were undergoing
apoptosis in control myocardium and 4000 per
106 after pacing. Moreover, DNA laddering was shown in
myocytes by agarose gel electrophoresis of DNA fragments.
Conclusions—The activation of p53 and p53-dependent genes may be
critical in the modulation of myocyte apoptosis in
pacing-induced heart failure.
© 1998 American Heart Association, Inc.
Basic Science Reports
Pacing-Induced Heart Failure in Dogs Enhances the Expression of p53 and p53-Dependent Genes in Ventricular Myocytes
Key Words: molecular biology • heart failure • apoptosis • pacing
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