Circulation, Vol 87, 454-463, Copyright © 1993 by American Heart Association
M Ungerer, M Bohm, JS Elce, E Erdmann and MJ Lohse
BACKGROUND. In chronic heart failure, the positive inotropic effects of
beta-adrenergic receptor agonists are greatly reduced, in part as a result
of two alterations of the cardiac beta-adrenergic receptors: loss of their
function (receptor uncoupling) and reduction of their number
(downregulation). In vitro studies have shown that a major mechanism
leading to beta-adrenergic receptor uncoupling involves phosphorylation of
the receptors by the specific beta-adrenergic receptor kinase (beta ARK).
METHODS AND RESULTS. We have therefore investigated expression of beta ARK
and beta-adrenergic receptors in samples from the left ventricles of
patients with dilated cardiomyopathy or ischemic cardiomyopathy and from
nonfailing control ventricles. Contractile responses to beta-receptor
stimulation were decreased in the failing hearts compared with control
hearts, whereas those to forskolin and calcium remained unchanged. The
messenger RNA (mRNA) levels of beta ARK, beta 1- and beta 2-receptors, and
of glyceraldehyde phosphate dehydrogenase and beta-actin as controls were
measured by quantitative polymerase chain reactions. In addition, beta ARK
enzyme activity assays were performed, and the levels of beta 1- and beta
2-receptors were determined by radioligand binding. beta ARK mRNA levels
were increased almost threefold in both forms of heart failure, and beta
ARK activity was enhanced. beta 1-Receptor mRNA levels and beta 1-receptor
numbers were decreased by approximately 50% in both failing groups, whereas
these levels were unaltered for beta 2- receptors. There were no
differences between dilated and ischemic cardiomyopathy for any of these
parameters. CONCLUSIONS. In addition to other alterations found in failing
hearts, the diminished response to beta-receptor agonists appears to
involve the combined effects of enhanced expression of beta ARK and reduced
expression of beta 1- receptors.
ARTICLES
Altered expression of beta-adrenergic receptor kinase and beta 1- adrenergic receptors in the failing human heart
Laboratorium fur Molekulare Biologie, Universitat Munchen, Max-Planck- Institut fur Biochemie, Martinsried, FRG.
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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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C. Maack, T. Elter, G. Nickenig, K. LaRosee, M. Crivaro, A. Stablein, H. Wuttke, and M. Bohm Prospective crossover comparison of carvedilol and metoprolol in patients with chronic heart failure J. Am. Coll. Cardiol., October 1, 2001; 38(4): 939 - 946. [Abstract] [Full Text] [PDF]
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H. Kubo, K. B. Margulies, V. Piacentino III, J. P. Gaughan, and S. R. Houser Patients With End-Stage Congestive Heart Failure Treated With {beta}-Adrenergic Receptor Antagonists Have Improved Ventricular Myocyte Calcium Regulatory Protein Abundance Circulation, August 28, 2001; 104(9): 1012 - 1018. [Abstract] [Full Text] [PDF]
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G. Iaccarino, E. Barbato, E. Cipolleta, A. Esposito, A. Fiorillo, W. J. Koch, and B. Trimarco Cardiac {beta}ARK1 Upregulation Induced by Chronic Salt Deprivation in Rats Hypertension, August 1, 2001; 38(2): 255 - 260. [Abstract] [Full Text] [PDF]
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I. Carrio Cardiac Neurotransmission Imaging J. Nucl. Med., July 1, 2001; 42(7): 1062 - 1076. [Abstract] [Full Text] [PDF]
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V. B. Harding, L. R. Jones, R. J. Lefkowitz, W. J. Koch, and H. A. Rockman Cardiac beta ARK1 inhibition prolongs survival and augments beta blocker therapy in a mouse model of severe heart failure PNAS, April 25, 2001; (2001) 91102398. [Abstract] [Full Text]
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E. P. Chen, H. B. Bittner, S. A. Akhter, W. J. Koch, and R. D. Davis Myocardial function in hearts with transgenic overexpression of the G protein-coupled receptor kinase 5 Ann. Thorac. Surg., April 1, 2001; 71(4): 1320 - 1324. [Abstract] [Full Text] [PDF]
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H. Yoshida, K. Tanonaka, Y. Miyamoto, T. Abe, M. Takahashi, M. B Anand-Srivastava, and S. Takeo Characterization of cardiac myocyte and tissue {beta}-adrenergic signal transduction in rats with heart failure Cardiovasc Res, April 1, 2001; 50(1): 34 - 45. [Abstract] [Full Text] [PDF]
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S. Moniotte, L. Kobzik, O. Feron, J.-N. Trochu, C. Gauthier, and J.-L. Balligand Upregulation of {beta}3-Adrenoceptors and Altered Contractile Response to Inotropic Amines in Human Failing Myocardium Circulation, March 27, 2001; 103(12): 1649 - 1655. [Abstract] [Full Text] [PDF]
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A. S. Shah, D. C. White, S. Emani, A. P. Kypson, R. E. Lilly, K. Wilson, D. D. Glower, R. J. Lefkowitz, and W. J. Koch In Vivo Ventricular Gene Delivery of a {beta}-Adrenergic Receptor Kinase Inhibitor to the Failing Heart Reverses Cardiac Dysfunction Circulation, March 6, 2001; 103(9): 1311 - 1316. [Abstract] [Full Text] [PDF]
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 P. Penela, M. Barradas, M. Alvarez-Dolado, A. Munoz, and F. Mayor Jr. Effect of Hypothyroidism on G Protein-Coupled Receptor Kinase 2 Expression Levels in Rat Liver, Lung, and Heart Endocrinology, March 1, 2001; 142(3): 987 - 991. [Abstract] [Full Text] [PDF]
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 S. S. G. Ferguson Evolving Concepts in G Protein-Coupled Receptor Endocytosis: The Role in Receptor Desensitization and Signaling Pharmacol. Rev., March 1, 2001; 53(1): 1 - 24. [Abstract] [Full Text] [PDF]
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 W. E. Schutzer, J. F. Reed, M. Bliziotes, and S. L. Mader Upregulation of G protein-linked receptor kinases with advancing age in rat aorta Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2001; 280(3): R897 - R903. [Abstract] [Full Text] [PDF]
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M. A. Gaballa, A. Eckhart, W. J. Koch, and S. Goldman Vascular {beta}-adrenergic receptor system is dysfunctional after myocardial infarction Am J Physiol Heart Circ Physiol, March 1, 2001; 280(3): H1129 - H1135. [Abstract] [Full Text] [PDF]
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M. R. Bristow Of Phospholamban, Mice, and Humans With Heart Failure Circulation, February 13, 2001; 103(6): 787 - 788. [Full Text] [PDF]
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 U. D. Dinçer, K. R. Bidasee, S. Güner, A. Tay, A. T. Özçelikay, and V. M. Altan The Effect of Diabetes on Expression of {beta}1-, {beta}2-, and {beta}3-Adrenoreceptors in Rat Hearts Diabetes, February 1, 2001; 50(2): 455 - 461. [Abstract] [Full Text]
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M. S. Lombardi, A. Kavelaars, P. M. Cobelens, R. E. Schmidt, M. Schedlowski, and C. J. Heijnen Adjuvant Arthritis Induces Down-Regulation of G Protein-Coupled Receptor Kinases in the Immune System J. Immunol., February 1, 2001; 166(3): 1635 - 1640. [Abstract] [Full Text] [PDF]
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M. Flesch, S. Ettelbruck, S. Rosenkranz, C. Maack, B. Cremers, K.-D. Schluter, O. Zolk, and M. Bohm Differential effects of carvedilol and metoprolol on isoprenaline-induced changes in {beta}-adrenoceptor density and systolic function in rat cardiac myocytes Cardiovasc Res, February 1, 2001; 49(2): 371 - 380. [Abstract] [Full Text] [PDF]
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S. Lutz, R. Mura, D. Baltus, M. Movsesian, W. Kubler, and F. Niroomand Increased activity of membrane-associated nucleoside diphosphate kinase and inhibition of cAMP synthesis in failing human myocardium Cardiovasc Res, January 1, 2001; 49(1): 48 - 55. [Abstract] [Full Text] [PDF]
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B. S. Manning, K. Shotwell, L. Mao, H. A. Rockman, and W. J. Koch Physiological Induction of a {beta}-Adrenergic Receptor Kinase Inhibitor Transgene Preserves {beta}-Adrenergic Responsiveness in Pressure-Overload Cardiac Hypertrophy Circulation, November 28, 2000; 102(22): 2751 - 2757. [Abstract] [Full Text] [PDF]
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A. S. Shah, D. C. White, O. Tai, J. A. Hata, K. H. Wilson, A. Pippen, A. P. Kypson, D. D. Glower, R. J. Lefkowitz, and W. J. Koch Adenovirus-mediated genetic manipulation of the myocardial {beta}-adrenergic signaling system in transplanted hearts J. Thorac. Cardiovasc. Surg., September 1, 2000; 120(3): 581 - 588. [Abstract] [Full Text] [PDF]
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H. Chen, Y. C. Zhang, D. Li, M. I. Phillips, P. Mehta, M. Shi, and J. L. Mehta Protection against Myocardial Dysfunction Induced by Global Ischemia-Reperfusion by Antisense-Oligodeoxynucleotides Directed at beta 1-Adrenoceptor mRNA J. Pharmacol. Exp. Ther., August 1, 2000; 294(2): 722 - 727. [Abstract] [Full Text]
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A. S. Shah, B. Z. Atkins, J. A. Hata, O. Tai, A. P. Kypson, R. E. Lilly, W. J. Koch, and D. D. Glower Early effects of right ventricular volume overload on ventricular performance and {beta}-adrenergic signaling J. Thorac. Cardiovasc. Surg., August 1, 2000; 120(2): 342 - 349. [Abstract] [Full Text] [PDF]
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R. Ramos-Ruiz, P. Penela, R. B. Penn, and F. Mayor Jr Analysis of the Human G Protein-Coupled Receptor Kinase 2 (GRK2) Gene Promoter : Regulation by Signal Transduction Systems in Aortic Smooth Muscle Cells Circulation, May 2, 2000; 101(17): 2083 - 2089. [Abstract] [Full Text] [PDF]
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T. Wichter, M. Schafers, C. G. Rhodes, M. Borggrefe, H. Lerch, A. A. Lammertsma, F. Hermansen, O. Schober, G. Breithardt, and P. G. Camici Abnormalities of Cardiac Sympathetic Innervation in Arrhythmogenic Right Ventricular Cardiomyopathy : Quantitative Assessment of Presynaptic Norepinephrine Reuptake and Postsynaptic {beta}-Adrenergic Receptor Density With Positron Emission Tomography Circulation, April 4, 2000; 101(13): 1552 - 1558. [Abstract] [Full Text] [PDF]
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H.-J. Weig, K.-L. Laugwitz, A. Moretti, K. Kronsbein, C. Stadele, S. Bruning, M. Seyfarth, T. Brill, A. Schomig, and M. Ungerer Enhanced Cardiac Contractility After Gene Transfer of V2 Vasopressin Receptors In Vivo by Ultrasound-Guided Injection or Transcoronary Delivery Circulation, April 4, 2000; 101(13): 1578 - 1585. [Abstract] [Full Text] [PDF]
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A. Elorza, S. Sarnago, and F. Mayor Jr. Agonist-Dependent Modulation of G Protein-Coupled Receptor Kinase 2 by Mitogen-Activated Protein Kinases Mol. Pharmacol., April 1, 2000; 57(4): 778 - 783. [Abstract] [Full Text]
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C. Depre and H. Taegtmeyer Metabolic aspects of programmed cell survival and cell death in the heart Cardiovasc Res, February 1, 2000; 45(3): 538 - 548. [Abstract] [Full Text] [PDF]
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U Ravens and D Dobrev Regulation of sarcoplasmic reticulum Ca2+-ATPase and phospholamban in the failing and nonfailing heart Cardiovasc Res, January 1, 2000; 45(1): 245 - 252. [Full Text] [PDF]
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