(Circulation. 1999;100:2210.)
© 1999 American Heart Association, Inc.
Brief Rapid Communications |
Opposing Effects of ß1- and ß2-Adrenergic Receptors on Cardiac Myocyte Apoptosis
Role of a Pertussis Toxin–Sensitive G Protein
From the Myocardial Biology Unit and Cardiovascular Division, Boston University Medical Center, Boston Veterans Affairs Medical Center and Boston University School of Medicine, Boston, Mass.
Correspondence to Wilson S. Colucci, MD, Boston University Medical Center, 88 E Newton St, Boston, MA 02118. E-mail wilson.colucci{at}bmc.org
Background—ß-Adrenergic receptor (ß-AR) stimulation increases apoptosis in adult rat cardiac (ventricular) myocytes (ARVMs) via activation of adenylyl cyclase. ß2-ARs may couple to a Gi-mediated signaling pathway that can oppose the actions of adenylyl cyclase.
Methods and Results—In ARVMs, ß-AR stimulation for 24 hours increased the number of apoptotic cells as measured by flow cytometry. ß-AR–stimulated apoptosis was abolished by the ß1-AR–selective antagonist CGP 20712A (P<0.05 versus ß-AR stimulation alone) but was potentiated by the ß2-AR–selective antagonist ICI 118,551 (P<0.05 versus ß-AR stimulation alone). The muscarinic agonist carbachol also prevented ß-AR–stimulated apoptosis (P<0.05 versus ß-AR stimulation alone), whereas pertussis toxin potentiated the apoptotic action of ß-AR stimulation (P<0.05 versus ß-AR stimulation alone) and prevented the antiapoptotic action of carbachol.
Conclusions—In ARVMs, stimulation of ß1-ARs increases apoptosis via a cAMP-dependent mechanism, whereas stimulation of ß2-ARs inhibits apoptosis via a Gi-coupled pathway. These findings have implications for the pathophysiology and treatment of myocardial failure.
Key Words: apoptosis • receptors, adrenergic, beta • myocytes • adenylyl cyclase • proteins
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A. Remondino, S. H. Kwon, C. Communal, D. R. Pimentel, D. B. Sawyer, K. Singh, and W. S. Colucci {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 Circ. Res., February 7, 2003; 92(2): 136 - 138. [Abstract] [Full Text] [PDF]
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 T. Cesetti, J. M. Hernandez-Guijo, P. Baldelli, V. Carabelli, and E. Carbone Opposite Action of beta 1- and beta 2-Adrenergic Receptors on CaV1 L-Channel Current in Rat Adrenal Chromaffin Cells J. Neurosci., January 1, 2003; 23(1): 73 - 83. [Abstract] [Full Text] [PDF]
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 M. L. Kukin {beta}-Blockers in Chronic Heart Failure: Considerations for Selecting an Agent Mayo Clin. Proc., November 1, 2002; 77(11): 1199 - 1206. [Abstract] [PDF]
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P. Chiari, V. Piriou, G. Hadour, C. Rodriguez, J. Loufouat, J.-J. Lehot, M. Ovize, and R. Ferrera Preservation of ischemia and isoflurane-induced preconditioning after brain death in rabbit hearts Am J Physiol Heart Circ Physiol, November 1, 2002; 283(5): H1769 - H1774. [Abstract] [Full Text] [PDF]
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Y. Xiang, V. O. Rybin, S. F. Steinberg, and B. Kobilka Caveolar Localization Dictates Physiologic Signaling of beta 2-Adrenoceptors in Neonatal Cardiac Myocytes J. Biol. Chem., September 6, 2002; 277(37): 34280 - 34286. [Abstract] [Full Text] [PDF]
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M. C. Levin, S. Marullo, O. Muntaner, B. Andersson, and Y. Magnusson The Myocardium-protective Gly-49 Variant of the beta 1-Adrenergic Receptor Exhibits Constitutive Activity and Increased Desensitization and Down-regulation J. Biol. Chem., August 16, 2002; 277(34): 30429 - 30435. [Abstract] [Full Text] [PDF]
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J. D. Kilts, T. Akazawa, M. D. Richardson, and M. M. Kwatra Age Increases Cardiac Galpha i2 Expression, Resulting in Enhanced Coupling to G Protein-coupled Receptors J. Biol. Chem., August 16, 2002; 277(34): 31257 - 31262. [Abstract] [Full Text] [PDF]
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E. N Dedkova, Y. Gao Wang, L. A Blatter, and S. L Lipsius Nitric oxide signalling by selective {beta}2-adrenoceptor stimulation prevents ACh-induced inhibition of {beta}2-stimulated Ca2+ current in cat atrial myocytes J. Physiol., August 1, 2002; 542(3): 711 - 723. [Abstract] [Full Text] [PDF]
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B. Yusta, J. Estall, and D. J. Drucker Glucagon-like Peptide-2 Receptor Activation Engages Bad and Glycogen Synthase Kinase-3 in a Protein Kinase A-dependent Manner and Prevents Apoptosis following Inhibition of Phosphatidylinositol 3-Kinase J. Biol. Chem., July 5, 2002; 277(28): 24896 - 24906. [Abstract] [Full Text] [PDF]
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 B. J. A. Janssen and J. F. M. Smits Autonomic control of blood pressure in mice: basic physiology and effects of genetic modification Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2002; 282(6): R1545 - R1564. [Abstract] [Full Text] [PDF]
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H. Gong, H. Sun, W. J. Koch, T. Rau, T. Eschenhagen, U. Ravens, J. F. Heubach, D. L. Adamson, and S. E. Harding Specific {beta}2AR Blocker ICI 118,551 Actively Decreases Contraction Through a Gi-Coupled Form of the {beta}2AR in Myocytes From Failing Human Heart Circulation, May 28, 2002; 105(21): 2497 - 2503. [Abstract] [Full Text] [PDF]
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P. Andreka, N. Aiyar, L. C. Olson, J. Q. Wei, M. S. Turner, K. A. Webster, E. H. Ohlstein, and N. H. Bishopric Bucindolol Displays Intrinsic Sympathomimetic Activity in Human Myocardium Circulation, May 21, 2002; 105(20): 2429 - 2434. [Abstract] [Full Text] [PDF]
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 S. Goldstein Benefits of {beta}-Blocker Therapy for Heart Failure: Weighing the Evidence Arch Intern Med, March 25, 2002; 162(6): 641 - 648. [Abstract] [Full Text] [PDF]
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L.-M. Zhang, Z. Wang, and S. Nattel Effects of sustained beta -adrenergic stimulation on ionic currents of cultured adult guinea pig cardiomyocytes Am J Physiol Heart Circ Physiol, March 1, 2002; 282(3): H880 - H889. [Abstract] [Full Text] [PDF]
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L. A Nikolaidis, T. Hentosz, A. Doverspike, R. Huerbin, C. Stolarski, Y.-T. Shen, and R. P Shannon Catecholamine stimulation is associated with impaired myocardial O2 utilization in heart failure Cardiovasc Res, February 1, 2002; 53(2): 392 - 404. [Abstract] [Full Text] [PDF]
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 B Andersson, B Gruner Svealv, M Scharin Tang, and R Mobini Longitudinal myocardial contraction improves early during titration with metoprolol CR/XL in patients with heart failure Heart, January 1, 2002; 87(1): 23 - 28. [Abstract] [Full Text] [PDF]
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P. K. Tithof, M. Elgayyar, H. M. Schuller, M. Barnhill, and R. Andrews 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone, a nicotine derivative, induces apoptosis of endothelial cells Am J Physiol Heart Circ Physiol, November 1, 2001; 281(5): H1946 - H1954. [Abstract] [Full Text] [PDF]
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 R.-P. Xiao {beta}-Adrenergic Signaling in the Heart: Dual Coupling of the {beta}2-Adrenergic Receptor to Gs and Gi Proteins Sci. Signal., October 16, 2001; 2001(104): re15 - re15. [Abstract] [Full Text] [PDF]
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A. D. Eckhart and W. J. Koch Transgenic Studies of Cardiac Adrenergic Receptor Regulation J. Pharmacol. Exp. Ther., October 1, 2001; 299(1): 1 - 5. [Abstract] [Full Text] [PDF]
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E. Devic, Y. Xiang, D. Gould, and B. Kobilka beta -Adrenergic Receptor Subtype-Specific Signaling in Cardiac Myocytes from beta 1 and beta 2 Adrenoceptor Knockout Mice Mol. Pharmacol., September 1, 2001; 60(3): 577 - 583. [Abstract] [Full Text] [PDF]
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F. Qin, N. K. Rounds, W. Mao, K. Kawai, and C.-s. Liang Antioxidant vitamins prevent cardiomyocyte apoptosis produced by norepinephrine infusion in ferrets Cardiovasc Res, September 1, 2001; 51(4): 736 - 748. [Abstract] [Full Text] [PDF]
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J. M. Hare Oxidative Stress and Apoptosis in Heart Failure Progression Circ. Res., August 3, 2001; 89(3): 198 - 200. [Full Text] [PDF]
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X.-J. Du Sympathoadrenergic mechanisms in functional regulation and development of cardiac hypertrophy and failure: findings from genetically engineered mice Cardiovasc Res, June 1, 2001; 50(3): 443 - 453. [Full Text] [PDF]
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D. M. Kaye, L. Johnston, G. Vaddadi, H. Brunner-LaRocca, G. L. Jennings, and M. D. Esler Mechanisms of Carvedilol Action in Human Congestive Heart Failure Hypertension, May 1, 2001; 37(5): 1216 - 1221. [Abstract] [Full Text] [PDF]
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M. Henaff, S. N. Hatem, and J.-J. Mercadier Low Catecholamine Concentrations Protect Adult Rat Ventricular Myocytes against Apoptosis through cAMP-Dependent Extracellular Signal-Regulated Kinase Activation Mol. Pharmacol., April 13, 2001; 58(6): 1546 - 1553. [Abstract] [Full Text]
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W.-Z. Zhu, M. Zheng, W. J. Koch, R. J. Lefkowitz, B. K. Kobilka, and R.-P. Xiao Dual modulation of cell survival and cell death by beta 2-adrenergic signaling in adult mouse cardiac myocytes PNAS, February 13, 2001; 98(4): 1607 - 1612. [Abstract] [Full Text] [PDF]
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M. Jain, C. C. Lim, K. Nagata, V. M. Davis, D. S. Milstone, R. Liao, and R. M. Mortensen Targeted inactivation of G{alpha}i does not alter cardiac function or {beta}-adrenergic sensitivity Am J Physiol Heart Circ Physiol, February 1, 2001; 280(2): H569 - H575. [Abstract] [Full Text] [PDF]
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M. Schafer, K. Ponicke, I. Heinroth-Hoffmann, O.-E. Brodde, H. M. Piper, and K.-D. Schluter Beta-adrenoceptor stimulation attenuates the hypertrophic effect of alpha-adrenoceptor stimulation in adult rat ventricular cardiomyocytes J. Am. Coll. Cardiol., January 1, 2001; 37(1): 300 - 307. [Abstract] [Full Text] [PDF]
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Y.-Y. Zhou and M. Artman Nucleoside diphosphate kinase: a new player in heart failure? Cardiovasc Res, January 1, 2001; 49(1): 7 - 10. [Full Text] [PDF]
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S. F. Steinberg The Cellular Actions of {beta}-Adrenergic Receptor Agonists : Looking Beyond cAMP Circ. Res., December 8, 2000; 87(12): 1079 - 1082. [Full Text] [PDF]
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A. Chesley, M. S. Lundberg, T. Asai, R.-P. Xiao, S. Ohtani, E. G. Lakatta, and M. T. Crow The {beta}2-Adrenergic Receptor Delivers an Antiapoptotic Signal to Cardiac Myocytes Through Gi-Dependent Coupling to Phosphatidylinositol 3'-Kinase Circ. Res., December 8, 2000; 87(12): 1172 - 1179. [Abstract] [Full Text] [PDF]
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X.-J. Du, X.-M. Gao, B. Wang, G. L Jennings, E. A Woodcock, and A. M Dart Age-dependent cardiomyopathy and heart failure phenotype in mice overexpressing {beta}2-adrenergic receptors in the heart Cardiovasc Res, December 1, 2000; 48(3): 448 - 454. [Abstract] [Full Text] [PDF]
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N.G. Mahon and W.J. Mckenna Genes and acquired disease: beta-adrenoceptor polymorphisms and heart failure Eur. Heart J., November 2, 2000; 21(22): 1810 - 1812. [PDF]
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H. N. Sabbah, V. G. Sharov, R. C. Gupta, A. Todor, V. Singh, and S. Goldstein Chronic therapy with metoprolol attenuates cardiomyocyte apoptosis in dogs with heart failure J. Am. Coll. Cardiol., November 1, 2000; 36(5): 1698 - 1705. [Abstract] [Full Text] [PDF]
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