(Circulation. 1999;100:305-311.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
- and ß-Adrenergic Pathways Differentially Regulate Cell Type–Specific Apoptosis in Rat Cardiac Myocytes
From the Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Correspondence to Koji Hasegawa, MD, PhD, Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, 54 Kawara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan. E-mail koj{at}kuhp.kyoto-u.ac.jp
Background—The apoptosis
of cardiac myocytes may play a role in the development of heart
failure. Norepinephrine is one of the factors
activated in heart failure and can induce myocardial cell
apoptosis in culture. However, it is unknown if 
- and
ß-adrenergic pathways coordinately or differentially regulate
apoptosis and if this apoptotic pathway uses common or
cell type–specific apoptotic signals.
Methods and Results—We stimulated cultured neonatal rat cardiac
myocytes with an 1-adrenergic agonist (PE,
phenylephrine), a ß-adrenergic agonist (isoproterenol
[Iso]) or a membrane-permeable cAMP analogue (8-Br-cAMP) in
serum-free conditions for 48 hours. Iso and 8-Br-cAMP markedly
increased the number of TUNEL-positive cells (%TUNEL-positive nuclei
>40%) compared with saline stimulation (<10%). DNA fragmentation
was also confirmed by ladder formation in agarose gels.
Apoptotic myocytes were characterized by cell shrinkage and
nuclear condensation, consistent with morphological features of
apoptosis. The Iso-induced apoptosis was almost
completely inhibited by the protein kinase A–specific
inhibitor KT5720. In contrast, PE inhibited
8-Br-cAMP–induced myocardial cell apoptosis. The
apoptosis-inhibitory effect by PE was negated by
the 1-adrenergic receptor antagonist
prazosin and the MEK-1–specific inhibitor PD098059.
Interestingly, although 8-Br-cAMP markedly induced apoptosis in
cardiac myocytes, it completely blocked serum depletion–induced
apoptosis in PC12 cells, a rat pheochromocytoma cell line.
Conclusions—These findings indicate that - and ß-adrenergic
pathways differentially regulate myocardial cell apoptosis. The
results also suggest that a cAMP– protein kinase A pathway is
necessary and sufficient for ß-adrenergic agonist–induced
apoptosis and that this apoptotic pathway is not
functional in other cell types, for example, PC12 cells.
Key Words: apoptosis • myocytes • heart failure
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