Circulation Research. 2003
Published online before print January 2, 2003, doi: 10.1161/01.RES.0000054624.03539.B4
Published online before print January 2, 2003, doi: 10.1161/01.RES.0000054624.03539.B4
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Submitted on October 29, 2002
Revised on December 17, 2002
Accepted on December 17, 2002
-Adrenergic Receptor-Stimulated Apoptosis in Cardiac Myocytes Is Mediated by Reactive Oxygen Species/c-Jun NH2-Terminal Kinase-Dependent Activation of the Mitochondrial Pathway
Andrea Remondino ;
From the Myocardial Biology Unit and Cardiovascular Medicine Section, Boston University Medical Center, Boston, Mass. Present address for K.S. is the Department of Physiology, East Tennessee State University, Johnson City, Tenn.
* To whom correspondence should be addressed. E-mail: wilson.colucci{at}bmc.org.
Stimulation of 
-adrenergic receptors (ARs) causes apoptosis in adult rat ventricular myocytes (ARVMs). The role of reactive oxygen species (ROS) in mediating AR-stimulated apoptosis is not known. Stimulation of ARs with norepinephrine (10 µmol/L) in the presence of prazosin (100 nmol/L) for 24 hours increased the number of apoptotic myocytes as determined by TUNEL staining by 3.6-fold. The superoxide dismutase/catalase mimetics Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin pentachloride (MnTMPyP; 10 µmol/L) and Euk-134 decreased AR-stimulated apoptosis by 89±6% and 76±10%, respectively. Infection with an adenovirus expressing catalase decreased AR-stimulated apoptosis by 82±15%. The mitochondrial permeability transition pore inhibitor bongkrekic acid (50 µmol/L) decreased AR-stimulated apoptosis by 76±8%, and the caspase inhibitor zVAD-fmk (25 µmol/L) decreased AR-stimulated apoptosis by 62±11%. AR-stimulated cytochrome c release was inhibited by MnTMPyP. AR stimulation caused c-Jun NH2-terminal kinase (JNK) activation, which was abolished by MnTMPyP. Transfection with an adenovirus expressing dominant-negative JNK inhibited AR-stimulated apoptosis by 81±12%, and the JNK inhibitor SP600125 inhibited both AR-stimulated apoptosis and cytochrome c release. Thus, AR-stimulated apoptosis in ARVMs involves ROS/JNK-dependent activation of the mitochondrial death pathway.
Key words: apoptosis •
-adrenergic receptors •
caspase •
c-Jun NH2-terminal kinase •
mitochondria •
myocytes •
reactive oxygen species
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