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(Circulation. 1999;99:2934-2941.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Signaling Pathways in Reactive Oxygen Species–Induced Cardiomyocyte Apoptosis
From the Department of Cardiology, Franz Volhard Clinic, Humboldt-University (R.v.H., R.D.), and the Max-Delbrück-Center for Molecular Medicine (P.-F.L.), Berlin, Germany.
Correspondence to Rüdiger von Harsdorf, MD, Franz-Volhard-Klinik, Medizinische Fakultät der Charité, Humboldt-Universität, Wiltbergstr. 50, 13125 Berlin, FRG. E-mail rharsdo{at}mdc-berlin.de
Background—The importance of free radical homeostasis and apoptosis in normal and diseased hearts and their interrelationships are poorly defined. We tested whether reactive oxygen species can trigger apoptosis in cardiomyocytes, and we explored the underlying pathways.
Methods and Results—A cell culture model of isolated cardiac
cells and different reactive oxygen species (ROS)–generating systems
were used. Apoptosis became evident when
cardiomyocytes were exposed to either
H2O2 or superoxide anion
(O2-). Both H2O2- and
O2--induced apoptosis of
cardiomyocytes were associated with an increase in p53
protein content, whereas protein levels of Bax and Bcl-2 were
unaltered. H2O2, but not
O2-, induced an increase in the protein
content of Bad. Furthermore, H2O2 elicited
translocation of Bax and Bad from cytosol to mitochondria, where these
factors formed heterodimers with Bcl-2, which was followed by the
release of cytochrome c, activation of CPP32, and
cleavage of poly(ADP-ribose) polymerase. Interestingly, this pathway
was not activated by O2-. Instead,
O2- used Mch2
to promote the
apoptotic pathway, as revealed by the activation of Mch2 and
the cleavage of its substrate, lamin A.
Conclusions—Taken together, these results indicate that ROS may play an important pathophysiological role in cardiac diseases characterized by apoptotic cell death and suggest that different ROS-induced activations of the apoptotic cell death program in cardiomyocytes involve distinct signaling pathways.
Key Words: myocytes • apoptosis • reactive oxygen species • cytochrome c
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