title: Beta-adrenergic receptor-stimulated apoptosis in cardiac myocytes is mediated by reactive oxygen species/c-Jun NH2-terminal kinase-dependent activation of the mitochondrial pathway.
abstract: Stimulation of beta-adrenergic receptors (betaARs) causes apoptosis in adult rat ventricular myocytes (ARVMs). The role of reactive oxygen species (ROS) in mediating betaAR-stimulated apoptosis is not known. Stimulation of betaARs with norepinephrine (10 micromol/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 micromol/L) and Euk-134 decreased betaAR-stimulated apoptosis by 89+/-6% and 76+/-10%, respectively. Infection with an adenovirus expressing catalase decreased betaAR-stimulated apoptosis by 82+/-15%. The mitochondrial permeability transition pore inhibitor bongkrekic acid (50 micromol/L) decreased betaAR-stimulated apoptosis by 76+/-8%, and the caspase inhibitor zVAD-fmk (25 micromol/L) decreased betaAR-stimulated apoptosis by 62+/-11%. betaAR-stimulated cytochrome c release was inhibited by MnTMPyP. betaAR stimulation caused c-Jun NH2-terminal kinase (JNK) activation, which was abolished by MnTMPyP. Transfection with an adenovirus expressing dominant-negative JNK inhibited betaAR-stimulated apoptosis by 81+/-12%, and the JNK inhibitor SP600125 inhibited both betaAR-stimulated apoptosis and cytochrome c release. Thus, betaAR-stimulated apoptosis in ARVMs involves ROS/JNK-dependent activation of the mitochondrial death pathway.
authors.affiliation: Myocardial Biology Unit and Cardiovascular Medicine Section, Boston University Medical Center, Boston, Mass 02118, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Remondino
authors.forename: Susan H
authors.initials: SH
authors.lastname: Kwon
authors.forename: Catherine
authors.initials: C
authors.lastname: Communal
authors.forename: David R
authors.initials: DR
authors.lastname: Pimentel
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Sawyer
authors.forename: Krishna
authors.initials: K
authors.lastname: Singh
authors.forename: Wilson S
authors.initials: WS
authors.lastname: Colucci
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001865:Bongkrekic Acid / Q000494:pharmacology; D061945:Caspase Inhibitors; D002374:Catalase / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D002478:Cells, Cultured; D003574:Cytochrome c Group / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D007473:Ion Channels / Q000037:antagonists & inhibitors; D048031:JNK Mitogen-Activated Protein Kinases; D008665:Metalloporphyrins / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D009638:Norepinephrine / Q000494:pharmacology; D009942:Organometallic Compounds / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism*; D012459:Salicylates / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology
chemical_list: D061945:Caspase Inhibitors; D003574:Cytochrome c Group; C433928:EUK-134; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D007473:Ion Channels; D008665:Metalloporphyrins; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D009942:Organometallic Compounds; D017382:Reactive Oxygen Species; D011943:Receptors, Adrenergic, beta; D012459:Salicylates; D001865:Bongkrekic Acid; C050950:tetrakis(N-methyl-4-pyridiniumyl)porphine manganese(III) complex; D002374:Catalase; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D009638:Norepinephrine; D011224:Prazosin