| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
From the Departments of Medicine (G.I., R.J.L.), Surgery (E.D.T, W.J.K.),
and Biochemistry (R.J.L.) and Howard Hughes Medical Institute, Duke University
Medical Center (R.J.L.), Durham, NC.
Correspondence to Walter J. Koch, PhD, Department of Surgery, Duke University Medical Center, Room 472, MSRB, Research Drive, Durham, NC 27710. E-mail koch0002{at}mc.duke.edu
Background—Impaired myocardial
ß-adrenergic receptor (ßAR) signaling, including desensitization
and functional uncoupling, is a characteristic of congestive heart
failure. A contributing mechanism for this impairment may involve
enhanced myocardial ß-adrenergic receptor kinase (ßARK1) activity
because levels of this ßAR-desensitizing G protein–coupled receptor
kinase (GRK) are increased in heart failure. An hypothesis has emerged
that increased sympathetic nervous system activity associated with
heart failure might be the initial stimulus for ßAR signaling
alterations, including desensitization. We have chronically treated
mice with drugs that either activate or antagonize ßARs to
study the dynamic relationship between ßAR activation and myocardial
levels of ßARK1.
Methods and Results—Long-term in vivo stimulation of ßARs
results in the impairment of cardiac ßAR signaling and
increases the level of expression (mRNA and protein) and activity of
ßARK1 but not that of GRK5, a second GRK abundantly expressed in the
myocardium. Long-term ß-blocker treatment, including the
use of carvedilol, improves myocardial ßAR signaling and reduces
ßARK1 levels in a specific and dose-dependent manner. Identical
results were obtained in vitro in cultured cells, demonstrating that
the regulation of GRK expression is directly linked to ßAR
signaling.
Conclusions—This report demonstrates, for the first time, that
ßAR stimulation can significantly increase the expression of ßARK1,
whereas ß-blockade decreases expression. This reciprocal regulation
of ßARK1 documents a novel mechanism of ligand-induced ßAR
regulation and provides important insights into the potential
mechanisms responsible for the effectiveness of ß-blockers, such as
carvedilol, in the treatment of heart failure.
© 1998 American Heart Association, Inc.
Basic Science Reports
Reciprocal In Vivo Regulation of Myocardial G Protein–Coupled Receptor Kinase Expression by ß-Adrenergic Receptor Stimulation and Blockade
Key Words: heart failure • receptors, adrenergic, beta • myocardium • catecholamines
This article has been cited by other articles:
 |
|
 |
|
  E. Cipolletta, A. Campanile, G. Santulli, E. Sanzari, D. Leosco, P. Campiglia, B. Trimarco, and G. Iaccarino The G protein coupled receptor kinase 2 plays an essential role in beta-adrenergic receptor-induced insulin resistance Cardiovasc Res, December 1, 2009; 84(3): 407 - 415. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Chen, J. Sroubek, Y. Krishnan, Y. Li, J. Bian, and T. V. McDonald PKA phosphorylation of HERG protein regulates the rate of channel synthesis Am J Physiol Heart Circ Physiol, May 1, 2009; 296(5): H1244 - H1254. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Rengo, A. Lymperopoulos, C. Zincarelli, M. Donniacuo, S. Soltys, J. E. Rabinowitz, and W. J. Koch Myocardial Adeno-Associated Virus Serotype 6-{beta}ARKct Gene Therapy Improves Cardiac Function and Normalizes the Neurohormonal Axis in Chronic Heart Failure Circulation, January 6, 2009; 119(1): 89 - 98. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Piscione, G. Iaccarino, G. Galasso, E. Cipolletta, M. A. Rao, G. Brevetti, R. Piccolo, B. Trimarco, and M. Chiariello Effects of Ile164 Polymorphism of Beta2-Adrenergic Receptor Gene on Coronary Artery Disease J. Am. Coll. Cardiol., October 21, 2008; 52(17): 1381 - 1388. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Metaye, P. Levillain, J.-L. Kraimps, and R. Perdrisot Immunohistochemical detection, regulation and antiproliferative function of G-protein-coupled receptor kinase 2 in thyroid carcinomas J. Endocrinol., July 1, 2008; 198(1): 101 - 110. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Leosco, G. Rengo, G. Iaccarino, L. Golino, M. Marchese, F. Fortunato, C. Zincarelli, E. Sanzari, M. Ciccarelli, G. Galasso, et al. Exercise promotes angiogenesis and improves {beta}-adrenergic receptor signalling in the post-ischaemic failing rat heart Cardiovasc Res, May 1, 2008; 78(2): 385 - 394. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. K. Pandalai, K. M. McLean, C. F. Bulcao, J. Y. Duffy, K. M. D'Souza, W. H. Merrill, J. M. Pearl, and S. A. Akhter Acute beta-blockade prevents myocardial beta-adrenergic receptor desensitization and preserves early ventricular function after brain death. J. Thorac. Cardiovasc. Surg., April 1, 2008; 135(4): 792 - 798. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Leosco, G. Rengo, G. Iaccarino, A. Filippelli, A. Lymperopoulos, C. Zincarelli, F. Fortunato, L. Golino, M. Marchese, G. Esposito, et al. Exercise training and beta-blocker treatment ameliorate age-dependent impairment of beta-adrenergic receptor signaling and enhance cardiac responsiveness to adrenergic stimulation Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1596 - H1603. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Yu, S. Huang, E. Patterson, M. W. Garrett, K. M. Kaufman, J. P. Metcalf, M. Zhu, S. T. Dunn, and D. C. Kem Proteasome degradation of GRK2 during ischemia and ventricular tachyarrhythmias in a canine model of myocardial infarction Am J Physiol Heart Circ Physiol, November 1, 2005; 289(5): H1960 - H1967. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. K. Pandalai, J. M. Lyons, J. Y. Duffy, K. M. McLean, C. J. Wagner, W. H. Merrill, J. M. Pearl, and S. A. Akhter Role of the {beta}-adrenergic receptor kinase in myocardial dysfunction after brain death J. Thorac. Cardiovasc. Surg., October 1, 2005; 130(4): 1183 - 1189. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Iaccarino, E. Barbato, E. Cipolletta, V. De Amicis, K. B. Margulies, D. Leosco, B. Trimarco, and W. J. Koch Elevated myocardial and lymphocyte GRK2 expression and activity in human heart failure Eur. Heart J., September 1, 2005; 26(17): 1752 - 1758. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Leineweber, P. Rohe, A. Beilfuss, C. Wolf, H. Sporkmann, H. Bruck, H.-G. Jakob, G. Heusch, T. Philipp, and O.-E. Brodde G-protein-coupled receptor kinase activity in human heart failure: Effects of {beta}-adrenoceptor blockade Cardiovasc Res, June 1, 2005; 66(3): 512 - 519. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Cheng, F. Qiao, T. N. Gallien, D. Kuppuswamy, and G. Cooper IV Inhibition of {beta}-adrenergic receptor trafficking in adult cardiocytes by MAP4 decoration of microtubules Am J Physiol Heart Circ Physiol, March 1, 2005; 288(3): H1193 - H1202. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. F. McBride and C. M. White Critical Differences Among Beta-Adrenoreceptor Antagonists in Myocardial Failure: Debating the MERIT of COMET J. Clin. Pharmacol., January 1, 2005; 45(1): 6 - 24. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Iaccarino, M. Ciccarelli, D. Sorriento, E. Cipolletta, V. Cerullo, G. L. Iovino, A. Paudice, A. Elia, G. Santulli, A. Campanile, et al. AKT Participates in Endothelial Dysfunction in Hypertension Circulation, June 1, 2004; 109(21): 2587 - 2593. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. L. Williams, J. A. Hata, J. Schroder, E. Rampersaud, J. Petrofski, A. Jakoi, C. A. Milano, and W. J. Koch Targeted {beta}-Adrenergic Receptor Kinase ({beta}ARK1) Inhibition by Gene Transfer in Failing Human Hearts Circulation, April 6, 2004; 109(13): 1590 - 1593. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. Emani, A. S. Shah, M. K. Bowman, D. C. White, S. Emani, D. D. Glower, and W. J. Koch Right ventricular targeted gene transfer of a {beta}-adrenergic receptor kinase inhibitor improves ventricular performance after pulmonary artery banding J. Thorac. Cardiovasc. Surg., March 1, 2004; 127(3): 787 - 793. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. W. Dorn II and J. D. Molkentin Manipulating Cardiac Contractility in Heart Failure: Data From Mice and Men Circulation, January 20, 2004; 109(2): 150 - 158. [Full Text] [PDF]
|
|
|
|
 |
|
 J.R. Keys and W.J. Koch The Adrenergic Pathway and Heart Failure Recent Prog. Horm. Res., January 1, 2004; 59(1): 13 - 30. [Abstract] [Full Text]
|
|
|
|
|
|
J. R. Keys, E. A. Greene, C. J. Cooper, S. V. Naga Prasad, H. A. Rockman, and W. J. Koch Cardiac hypertrophy and altered {beta}-adrenergic signaling in transgenic mice that express the amino terminus of {beta}-ARK1 Am J Physiol Heart Circ Physiol, November 1, 2003; 285(5): H2201 - H2211. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. Hata and W. J. Koch Phosphorylation of G Protein-Coupled Receptors: GPCR Kinases in Heart Disease Mol. Interv., August 1, 2003; 3(5): 264 - 272. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. W. Hughes, A. Sherwood, J. A. Blumenthal, E. C. Suarez, and A. L. Hinderliter Hostility, Social Support, and Adrenergic Receptor Responsiveness Among African-American and White Men and Women Psychosom Med, July 1, 2003; 65(4): 582 - 587. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Makino, Y. Hattori, N. Matsuda, H. Onozuka, I. Sakuma, and A. Kitabatake Effects of Angiotensin-Converting Enzyme Inhibition and Angiotensin II Type 1 Receptor Blockade on beta -Adrenoceptor Signaling in Heart Failure Produced by Myocardial Infarction in Rabbits: Reversal of Altered Expression of beta -Adrenoceptor Kinase and Gialpha J. Pharmacol. Exp. Ther., January 1, 2003; 304(1): 370 - 379. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. R. Keys, E. A. Greene, W. J. Koch, and A. D. Eckhart Gq-Coupled Receptor Agonists Mediate Cardiac Hypertrophy Via the Vasculature Hypertension, November 1, 2002; 40(5): 660 - 666. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Iaccarino, E. Cipolletta, A. Fiorillo, M. Annecchiarico, M. Ciccarelli, V. Cimini, W. J. Koch, and B. Trimarco {beta}2-Adrenergic Receptor Gene Delivery to the Endothelium Corrects Impaired Adrenergic Vasorelaxation in Hypertension Circulation, July 16, 2002; 106(3): 349 - 355. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Cogliati, D. J. Good, M. Haigney, P. Delgado-Romero, M. A. Eckhaus, W. J. Koch, and I. R. Kirsch Predisposition to Arrhythmia and Autonomic Dysfunction in Nhlh1-Deficient Mice Mol. Cell. Biol., July 15, 2002; 22(14): 4977 - 4983. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Jourdain, F. Funck, Y. Fulla, A. Hagege, M. Bellorini, N. Guillard, J. Loiret, B. Thebault, and M. Desnos Myocardial contractile reserve under low doses of dobutamine and improvement of left ventricular ejection fraction with treatment by carvedilol Eur J Heart Fail, June 1, 2002; 4(3): 269 - 276. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Leineweber, I. Heinroth-Hoffmann, K. Ponicke, G. Abraham, B. Osten, and O.-E. Brodde Cardiac {beta}-Adrenoceptor Desensitization Due to Increased {beta}-Adrenoceptor Kinase Activity in Chronic Uremia J. Am. Soc. Nephrol., January 1, 2002; 13(1): 117 - 124. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. T. Tevaearai, A. D. Eckhart, K. F. Shotwell, K. Wilson, and W. J. Koch Ventricular Dysfunction After Cardioplegic Arrest Is Improved After Myocardial Gene Transfer of a {beta}-Adrenergic Receptor Kinase Inhibitor Circulation, October 23, 2001; 104(17): 2069 - 2074. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
G. Iaccarino, J. R. Keys, A. Rapacciuolo, K. F. Shotwell, R. J. Lefkowitz, H. A. Rockman, and W. J. Koch Regulation of myocardial {beta}ARK1 expression in catecholamine-induced cardiac hypertrophy in transgenic mice overexpressing {alpha}1B-adrenergic receptors J. Am. Coll. Cardiol., August 1, 2001; 38(2): 534 - 540. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 M. Iwata, T. Yoshikawa, A. Baba, T. Anzai, I. Nakamura, Y. Wainai, T. Takahashi, and S. Ogawa Autoimmunity Against the Second Extracellular Loop of {beta}1-Adrenergic Receptors Induces {beta}-Adrenergic Receptor Desensitization and Myocardial Hypertrophy In Vivo Circ. Res., March 30, 2001; 88(6): 578 - 586. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
K. Freeman, C. Colon-Rivera, M. C. Olsson, R. L. Moore, H. D. Weinberger, I. L. Grupp, K. L. Vikstrom, G. Iaccarino, W. J. Koch, and L. A. Leinwand Progression from hypertrophic to dilated cardiomyopathy in mice that express a mutant myosin transgene Am J Physiol Heart Circ Physiol, January 1, 2001; 280(1): H151 - H159. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
X. Yu, M. Zhang, K. Kyker, E. Patterson, J. L. Benovic, and D. C. Kem Ischemic Inactivation of G Protein-Coupled Receptor Kinase and Altered Desensitization of Canine Cardiac {beta}-Adrenergic Receptors Circulation, November 14, 2000; 102(20): 2535 - 2540. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X.-J. Du, X.-M. Gao, G. L. Jennings, A. M. Dart, and E. A. Woodcock Preserved ventricular contractility in infarcted mouse heart overexpressing beta 2-adrenergic receptors Am J Physiol Heart Circ Physiol, November 1, 2000; 279(5): H2456 - H2463. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
R. J. Lefkowitz, H. A. Rockman, and W. J. Koch Catecholamines, Cardiac {beta}-Adrenergic Receptors, and Heart Failure Circulation, April 11, 2000; 101(14): 1634 - 1637. [Full Text] [PDF]
|
|
|
|
|
|
M. Ungerer, H.-J. Weig, S. Kubert, M. Overbeck, F. Bengel, A. Schomig, and M. Schwaiger Regional pre- and postsynaptic sympathetic system in the failing human heart -- regulation of {beta}ARK-1 Eur J Heart Fail, March 1, 2000; 2(1): 23 - 31. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Kavelaars, W. Kuis, L. Knook, G. Sinnema, and C. J. Heijnen Disturbed Neuroendocrine-Immune Interactions in Chronic Fatigue Syndrome J. Clin. Endocrinol. Metab., February 1, 2000; 85(2): 692 - 696. [Abstract] [Full Text]
|
|
|
|
|
|
A. S. Shah, R. E. Lilly, A. P. Kypson, O. Tai, J. A. Hata, A. Pippen, S. C. Silvestry, R. J. Lefkowitz, D. D. Glower, and W. J. Koch Intracoronary Adenovirus-Mediated Delivery and Overexpression of the {beta}2-Adrenergic Receptor in the Heart : Prospects for Molecular Ventricular Assistance Circulation, February 1, 2000; 101(4): 408 - 414. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X.-J. Du, D. J. Autelitano, R. J. Dilley, B. Wang, A. M. Dart, and E. A. Woodcock {beta}2-Adrenergic Receptor Overexpression Exacerbates Development of Heart Failure After Aortic Stenosis Circulation, January 4, 2000; 101(1): 71 - 77. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O.-E. Brodde and M. C. Michel Adrenergic and Muscarinic Receptors in the Human Heart Pharmacol. Rev., December 1, 1999; 51(4): 651 - 690. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Feldman and C. McTiernan New Insight Into the Role of Enhanced Adrenergic Receptor-Effector Coupling in the Heart Circulation, August 10, 1999; 100(6): 579 - 582. [Full Text] [PDF]
|
|
|
|
|
|
S. A. Akhter, A. D. Eckhart, H. A. Rockman, K. Shotwell, R. J. Lefkowitz, and W. J. Koch In Vivo Inhibition of Elevated Myocardial {beta}-Adrenergic Receptor Kinase Activity in Hybrid Transgenic Mice Restores Normal {beta}-Adrenergic Signaling and Function Circulation, August 10, 1999; 100(6): 648 - 653. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. P. Maurice, A. S. Shah, A. P. Kypson, J. A. Hata, D. C. White, D. D. Glower, and W. J. Koch Molecular beta -adrenergic signaling abnormalities in failing rabbit hearts after infarction Am J Physiol Heart Circ Physiol, June 1, 1999; 276(6): H1853 - H1860. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.-C. Cho, M. Rao, W. J. Koch, S. A. Thomas, R. D. Palmiter, and H. A. Rockman Enhanced Contractility and Decreased ß-Adrenergic Receptor Kinase-1 in Mice Lacking Endogenous Norepinephrine and Epinephrine Circulation, May 25, 1999; 99(20): 2702 - 2707. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Bunemann and M M. Hosey G-protein coupled receptor kinases as modulators of G-protein signalling J. Physiol., May 15, 1999; 517(1): 5 - 23. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Iaccarino, P. C. Dolber, R. J. Lefkowitz, and W. J. Koch ß-Adrenergic Receptor Kinase-1 Levels in Catecholamine-Induced Myocardial Hypertrophy : Regulation by ß- but not {alpha}1-Adrenergic Stimulation Hypertension, January 1, 1999; 33(1): 396 - 401. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. C. White, J. A. Hata, A. S. Shah, D. D. Glower, R. J. Lefkowitz, and W. J. Koch Preservation of myocardial beta -adrenergic receptor signaling delays the development of heart failure after myocardial infarction PNAS, May 9, 2000; 97(10): 5428 - 5433. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Yaoita, A. Sakabe, K. Maehara, and Y. Maruyama Different Effects of Carvedilol, Metoprolol, and Propranolol on Left Ventricular Remodeling After Coronary Stenosis or After Permanent Coronary Occlusion in Rats Circulation, February 26, 2002; 105(8): 975 - 980. [Abstract] [Full Text] [PDF]
|
|