(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
This article has been cited by other articles:
 |
|
 |
|
  B. Olshansky, H. N. Sabbah, P. J. Hauptman, and W. S. Colucci Parasympathetic Nervous System and Heart Failure: Pathophysiology and Potential Implications for Therapy Circulation, August 19, 2008; 118(8): 863 - 871. [Full Text] [PDF]
|
|
|
|
|
|
I. Kindermann, M. Kindermann, R. Kandolf, K. Klingel, B. Bultmann, T. Muller, A. Lindinger, and M. Bohm Predictors of Outcome in Patients With Suspected Myocarditis Circulation, August 5, 2008; 118(6): 639 - 648. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. E. Vinge, P. W. Raake, and W. J. Koch Gene Therapy in Heart Failure Circ. Res., June 20, 2008; 102(12): 1458 - 1470. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Poldermans, S. E. Hoeks, and H. H. Feringa Pre-Operative Risk Assessment and Risk Reduction Before Surgery J. Am. Coll. Cardiol., May 20, 2008; 51(20): 1913 - 1924. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Ahmet, M. Krawczyk, W. Zhu, A. Y.-H. Woo, C. Morrell, S. Poosala, R.-p. Xiao, E. G. Lakatta, and M. I. Talan Cardioprotective and Survival Benefits of Long-Term Combined Therapy with {beta}2 Adrenoreceptor (AR) Agonist and {beta}1 AR Blocker in Dilated Cardiomyopathy Postmyocardial Infarction J. Pharmacol. Exp. Ther., May 1, 2008; 325(2): 491 - 499. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. S. Lynch and J. G. Ryall Role of {beta}-Adrenoceptor Signaling in Skeletal Muscle: Implications for Muscle Wasting and Disease Physiol Rev, April 1, 2008; 88(2): 729 - 767. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Morisco, C. Marrone, V. Trimarco, S. Crispo, M. G. Monti, J. Sadoshima, and B. Trimarco Insulin resistance affects the cytoprotective effect of insulin in cardiomyocytes through an impairment of MAPK phosphatase-1 expression Cardiovasc Res, December 1, 2007; 76(3): 453 - 464. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X.-H. Zhang, G.-R. Li, and J.-P. Bourreau The effect of adrenomedullin on the L-type calcium current in myocytes from septic shock rats: signaling pathway Am J Physiol Heart Circ Physiol, November 1, 2007; 293(5): H2888 - H2893. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.-H. Huang, H.-Q. Wang, W. R. Roeske, Y. Birnbaum, Y. Wu, N.-P. Yang, Y. Lin, Y. Ye, D. J. McAdoo, M. G. Hughes, et al. Mediating {delta}-opioid-initiated heart protection via the beta2-adrenergic receptor: role of the intrinsic cardiac adrenergic cell Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H376 - H384. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Srivastava, B. Chandrasekar, Y. Gu, J. Luo, T. Hamid, B. G. Hill, and S. D. Prabhu Downregulation of CuZn-superoxide dismutase contributes to {beta}-adrenergic receptor-mediated oxidative stress in the heart Cardiovasc Res, June 1, 2007; 74(3): 445 - 455. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. F. Spear, S. K. Prabu, D. Galati, H. Raza, H. K. Anandatheerthavarada, and N. G. Avadhani beta1-Adrenoreceptor activation contributes to ischemia-reperfusion damage as well as playing a role in ischemic preconditioning Am J Physiol Heart Circ Physiol, May 1, 2007; 292(5): H2459 - H2466. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Huang, C. D. Wright, C. L. Merkwan, N. L. Baye, Q. Liang, P. C. Simpson, and T. D. O'Connell An {alpha}1A-Adrenergic-Extracellular Signal-Regulated Kinase Survival Signaling Pathway in Cardiac Myocytes Circulation, February 13, 2007; 115(6): 763 - 772. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. O. Nikolaev, M. Bunemann, E. Schmitteckert, M. J. Lohse, and S. Engelhardt Cyclic AMP Imaging in Adult Cardiac Myocytes Reveals Far-Reaching {beta}1-Adrenergic but Locally Confined {beta}2-Adrenergic Receptor-Mediated Signaling Circ. Res., November 10, 2006; 99(10): 1084 - 1091. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Nishii, T. Inomata, H. Niwano, H. Takehana, I. Takeuchi, H. Nakano, H. Shinagawa, T. Naruke, T. Koitabashi, J.-i. Nakahata, et al. {beta}2-Adrenergic Agonists Suppress Rat Autoimmune Myocarditis: Potential Role of {beta}2-Adrenergic Stimulants as New Therapeutic Agents for Myocarditis Circulation, August 29, 2006; 114(9): 936 - 944. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. J. Smith and L. M. Luttrell Signal Switching, Crosstalk, and Arrestin Scaffolds: Novel G Protein-Coupled Receptor Signaling in Cardiovascular Disease Hypertension, August 1, 2006; 48(2): 173 - 179. [Full Text] [PDF]
|
|
|
|
 |
|
 F. Giallauria, R. Lucci, M. Pietrosante, G. Gargiulo, A. De Lorenzo, M. D'Agostino, G. Gerundo, P. Abete, F. Rengo, and C. Vigorito Exercise-based cardiac rehabilitation improves heart rate recovery in elderly patients after acute myocardial infarction. J. Gerontol. A Biol. Sci. Med. Sci., July 1, 2006; 61(7): 713 - 717. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. D. Pierce, C. Goodyear-Bruch, S. Hall, and R. L. Clancy Effect of dopamine on rat diaphragm apoptosis and muscle performance Exp Physiol, July 1, 2006; 91(4): 731 - 740. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. S. George and G. S. Pitt The real estate of cardiac signaling: Location, location, location PNAS, May 16, 2006; 103(20): 7535 - 7536. [Full Text] [PDF]
|
|
|
|
|
|
S. Xydas, A. R. Kherani, J. S. Chang, S. Klotz, I. Hay, C. J. Mutrie, G. W. Moss, A. Gu, A. R. Schulman, D. Gao, et al. beta2-Adrenergic Stimulation Attenuates Left Ventricular Remodeling, Decreases Apoptosis, and Improves Calcium Homeostasis in a Rodent Model of Ischemic Cardiomyopathy J. Pharmacol. Exp. Ther., May 1, 2006; 317(2): 553 - 561. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Mittra and J.-P. Bourreau Gs and Gi coupling of adrenomedullin in adult rat ventricular myocytes Am J Physiol Heart Circ Physiol, May 1, 2006; 290(5): H1842 - H1847. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. M. Filipeanu, F. Zhou, M. L. Lam, K. E. Kerut, W. C. Claycomb, and G. Wu Enhancement of the Recycling and Activation of beta-Adrenergic Receptor by Rab4 GTPase in Cardiac Myocytes J. Biol. Chem., April 21, 2006; 281(16): 11097 - 11103. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. He, M. Bellini, H. Inuzuka, J. Xu, Y. Xiong, X. Yang, A. M. Castleberry, and R. A. Hall Proteomic Analysis of beta1-Adrenergic Receptor Interactions with PDZ Scaffold Proteins J. Biol. Chem., February 3, 2006; 281(5): 2820 - 2827. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Menon, M. Singh, R. S. Ross, J. N. Johnson, and K. Singh {beta}-Adrenergic receptor-stimulated apoptosis in adult cardiac myocytes involves MMP-2-mediated disruption of {beta}1 integrin signaling and mitochondrial pathway Am J Physiol Cell Physiol, January 1, 2006; 290(1): C254 - C261. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Bernstein, G. Fajardo, M. Zhao, T. Urashima, J. Powers, G. Berry, and B. K. Kobilka Differential cardioprotective/cardiotoxic effects mediated by {beta}-adrenergic receptor subtypes Am J Physiol Heart Circ Physiol, December 1, 2005; 289(6): H2441 - H2449. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-T. Tseng, N. Yano, A. Rojan, J. P. Stabila, B. G. McGonnigal, V. Ianus, R. Wadhawan, and J. F. Padbury Ontogeny of phosphoinositide 3-kinase signaling in developing heart: effect of acute {beta}-adrenergic stimulation Am J Physiol Heart Circ Physiol, November 1, 2005; 289(5): H1834 - H1842. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Wettschureck and S. Offermanns Mammalian G Proteins and Their Cell Type Specific Functions Physiol Rev, October 1, 2005; 85(4): 1159 - 1204. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Zhu, X. Zeng, M. Zheng, and R.-P. Xiao The Enigma of {beta}2-Adrenergic Receptor Gi Signaling in the Heart: The Good, the Bad, and the Ugly Circ. Res., September 16, 2005; 97(6): 507 - 509. [Full Text] [PDF]
|
|
|
|
|
|
J.-Q. He, R. C. Balijepalli, R. A. Haworth, and T. J. Kamp Crosstalk of {beta}-Adrenergic Receptor Subtypes Through Gi Blunts {beta}-Adrenergic Stimulation of L-Type Ca2+ Channels in Canine Heart Failure Circ. Res., September 16, 2005; 97(6): 566 - 573. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. McConville, R. G. Spencer, and E. G. Lakatta Temporal dynamics of inotropic, chronotropic, and metabolic responses during {beta}1- and {beta}2-AR stimulation in the isolated, perfused rat heart Am J Physiol Endocrinol Metab, September 1, 2005; 289(3): E412 - E418. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W.-Z. Zhu, K. Chakir, S. Zhang, D. Yang, C. Lavoie, M. Bouvier, T. E. Hebert, E. G. Lakatta, H. Cheng, and R.-P. Xiao Heterodimerization of {beta}1- and {beta}2-Adrenergic Receptor Subtypes Optimizes {beta}-Adrenergic Modulation of Cardiac Contractility Circ. Res., August 5, 2005; 97(3): 244 - 251. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Ding, J.-i. Abe, H. Wei, Q. Huang, R. A. Walsh, C. A. Molina, A. Zhao, J. Sadoshima, B. C. Blaxall, B. C. Berk, et al. Functional Role of Phosphodiesterase 3 in Cardiomyocyte Apoptosis: Implication in Heart Failure Circulation, May 17, 2005; 111(19): 2469 - 2476. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Ait-Mamar, M. Cailleret, C. Rucker-Martin, A. Bouabdallah, G. Candiani, C. Adamy, P. Duvaldestin, F. Pecker, N. Defer, and C. Pavoine The Cytosolic Phospholipase A2 Pathway, a Safeguard of {beta}2-Adrenergic Cardiac Effects in Rat J. Biol. Chem., May 13, 2005; 280(19): 18881 - 18890. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Machida, H. Inoue, K. Matsumoto, M. Tsuda, S. Fukuyama, H. Koto, H. Aizawa, Y. Kureishi, N. Hara, and Y. Nakanishi Activation of PI3K-Akt pathway mediates antiapoptotic effects of {beta}-adrenergic agonist in airway eosinophils Am J Physiol Lung Cell Mol Physiol, May 1, 2005; 288(5): L860 - L867. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Wang, Y.-H. Feng, and G. I. Gorodeski Epidermal Growth Factor Facilitates Epinephrine Inhibition of P2X7-Receptor-Mediated Pore Formation and Apoptosis: A Novel Signaling Network Endocrinology, January 1, 2005; 146(1): 164 - 174. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Leblais, S.-H. Jo, K. Chakir, V. Maltsev, M. Zheng, M. T. Crow, W. Wang, E. G. Lakatta, and R.-P. Xiao Phosphatidylinositol 3-Kinase Offsets cAMP-Mediated Positive Inotropic Effect via Inhibiting Ca2+ Influx in Cardiomyocytes Circ. Res., December 10, 2004; 95(12): 1183 - 1190. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Iwatsubo, S. Minamisawa, T. Tsunematsu, M. Nakagome, Y. Toya, J. E. Tomlinson, S. Umemura, R. M. Scarborough, D. E. Levy, and Y. Ishikawa Direct Inhibition of Type 5 Adenylyl Cyclase Prevents Myocardial Apoptosis without Functional Deterioration J. Biol. Chem., September 24, 2004; 279(39): 40938 - 40945. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Covolo, U. Gelatti, M. Metra, S. Nodari, A. Piccichè, N. Pezzali, C. Zani, A. Alberti, F. Donato, G. Nardi, et al. Role of {beta}1- and {beta}2-adrenoceptor polymorphisms in heart failure: a case-control study Eur. Heart J., September 1, 2004; 25(17): 1534 - 1541. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Ahmet, M. Krawczyk, P. Heller, C. Moon, E. G. Lakatta, and M. I. Talan Beneficial Effects of Chronic Pharmacological Manipulation of {beta}-Adrenoreceptor Subtype Signaling in Rodent Dilated Ischemic Cardiomyopathy Circulation, August 31, 2004; 110(9): 1083 - 1090. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Barki-Harrington, C. Perrino, and H. A Rockman Network integration of the adrenergic system in cardiac hypertrophy Cardiovasc Res, August 15, 2004; 63(3): 391 - 402. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Pepe, O. W.V van den Brink, E. G Lakatta, and R.-P. Xiao Cross-talk of opioid peptide receptor and {beta}-adrenergic receptor signalling in the heart Cardiovasc Res, August 15, 2004; 63(3): 414 - 422. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Ito, T. Adachi, D. R. Pimentel, Y. Ido, and W. S. Colucci Statins Inhibit {beta}-Adrenergic Receptor-Stimulated Apoptosis in Adult Rat Ventricular Myocytes via a Rac1-Dependent Mechanism Circulation, July 27, 2004; 110(4): 412 - 418. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A Movsesian Altered cAMP-mediated signalling and its role in the pathogenesis of dilated cardiomyopathy Cardiovasc Res, June 1, 2004; 62(3): 450 - 459. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. F. Heubach, U. Ravens, and A. J. Kaumann Epinephrine Activates Both Gs and Gi Pathways, but Norepinephrine Activates Only the Gs Pathway through Human {beta}2-Adrenoceptors Overexpressed in Mouse Heart Mol. Pharmacol., May 1, 2004; 65(5): 1313 - 1322. [Abstract] [Full Text]
|
|
|
|
|
|
A. El-Armouche, O. Zolk, T. Rau, and T. Eschenhagen Inhibitory G-proteins and their role in desensitization of the adenylyl cyclase pathway in heart failure Cardiovasc Res, December 1, 2003; 60(3): 478 - 487. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Foerster, F. Groner, J. Matthes, W. J. Koch, L. Birnbaumer, and S. Herzig Cardioprotection specific for the G protein Gi2 in chronic adrenergic signaling through {beta}2-adrenoceptors PNAS, November 25, 2003; 100(24): 14475 - 14480. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Lohse, S. Engelhardt, and T. Eschenhagen What Is the Role of {beta}-Adrenergic Signaling in Heart Failure? Circ. Res., November 14, 2003; 93(10): 896 - 906. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Pavoine, N. Behforouz, C. Gauthier, S. Le Gouvello, F. Roudot-Thoraval, C. R. Martin, A. Pawlak, C. Feral, N. Defer, R. Houel, et al. {beta}2-Adrenergic Signaling in Human Heart: Shift from the Cyclic AMP to the Arachidonic Acid Pathway Mol. Pharmacol., November 1, 2003; 64(5): 1117 - 1125. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Liang, S. Austin, Q. Hoang, and P. H. Fishman Resistance of the Human {beta}1-Adrenergic Receptor to Agonist-mediated Down-regulation: ROLE OF THE C TERMINUS IN DETERMINING {beta}-SUBTYPE DEGRADATION J. Biol. Chem., October 10, 2003; 278(41): 39773 - 39781. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R.-P. Xiao, S.-J. Zhang, K. Chakir, P. Avdonin, W. Zhu, R. A. Bond, C. W. Balke, E. G. Lakatta, and H. Cheng Enhanced Gi Signaling Selectively Negates {beta}2-Adrenergic Receptor (AR)- but Not {beta}1-AR-Mediated Positive Inotropic Effect in Myocytes From Failing Rat Hearts Circulation, September 30, 2003; 108(13): 1633 - 1639. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Manfrini, C. Pizzi, D. Trere, F. Fontana, and R. Bugiardini Parasympathetic failure and risk of subsequent coronary events in unstable angina and non-ST-segment elevation myocardial infarction Eur. Heart J., September 1, 2003; 24(17): 1560 - 1566. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Maack, M. Bohm, L. Vlaskin, E. Dabew, K. Lorenz, H.-J. Schafers, M. J. Lohse, and S. Engelhardt Partial Agonist Activity of Bucindolol Is Dependent on the Activation State of the Human {beta}1-Adrenergic Receptor Circulation, July 22, 2003; 108(3): 348 - 353. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. A. Hu, W. Chen, N. P. Martin, E. J. Whalen, R. T. Premont, and R. J. Lefkowitz GIPC Interacts with the {beta}1-Adrenergic Receptor and Regulates {beta}1-Adrenergic Receptor-mediated ERK Activation J. Biol. Chem., July 3, 2003; 278(28): 26295 - 26301. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Abbate, G. G. L. Biondi-Zoccai, R. Bussani, A. Dobrina, D. Camilot, F. Feroce, R. Rossiello, F. Baldi, F. Silvestri, L. M. Biasucci, et al. Increased myocardial apoptosis in patients with unfavorable left ventricular remodeling and early symptomatic post-infarction heart failure J. Am. Coll. Cardiol., March 5, 2003; 41(5): 753 - 760. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
P. Chiari, V. Piriou, G. Hadour, C. Rodriguez, J. Loufouat, J.-J. Lehot, M. Ovi |