Circulation. 2001;104:2843-2848
doi: 10.1161/hc4701.099578
doi: 10.1161/hc4701.099578
(Circulation. 2001;104:2843.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
ß-Adrenergic Receptor Blockers Restore Cardiac Calcium Release Channel (Ryanodine Receptor) Structure and Function in Heart Failure
From the Center for Molecular Cardiology (S.R., M.G., J.G., A.P., A.R.M.), Department of Pharmacology (A.R.M.), and Circulatory Physiology Division (K.H., E.B., G.Y., J.W., D.B.), Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY.
Correspondence to Andrew R. Marks, Center for Molecular Cardiology, Box 65, Columbia University College of Physicians and Surgeons, Room 9-401, 630 W 168th St, New York, NY 10032. E-mail arm42{at}columbia.edu
Background— ß-Adrenergic receptor blockade is one of the most effective treatments for heart failure, a leading cause of mortality worldwide. The use of ß-adrenergic receptor blockers in patients with heart failure is counterintuitive, however, because they are known to decrease contractility in normal hearts. The ryanodine receptor (RyR2) on cardiac sarcoplasmic reticulum is the key calcium release channel required for excitation-contraction coupling. In failing hearts, the stoichiometry and function of the RyR2 macromolecular complex is altered. Decreased levels of phosphatases (PP1 and PP2A) and hyperphosphorylation by protein kinase A result in dissociation of the regulatory protein FKBP12.6 and channels with increased open probability.
Methods and Results— Here, we show that systemic oral administration of a ß-adrenergic receptor blocker reverses protein kinase A hyperphosphorylation of RyR2, restores the stoichiometry of the RyR2 macromolecular complex, and normalizes single-channel function in a canine model of heart failure.
Conclusions— These results may, in part, explain the improved cardiac function observed in heart failure patients treated with ß-adrenergic receptor blockers.
Key Words: heart failure • calcium • sarcoplasmic reticulum • ion channels • receptors, adrenergic, beta
This article has been cited by other articles:
 |
|
 |
|
  A. M. Gomez, A. Rueda, Y. Sainte-Marie, L. Pereira, S. Zissimopoulos, X. Zhu, R. Schaub, E. Perrier, R. Perrier, C. Latouche, et al. Mineralocorticoid Modulation of Cardiac Ryanodine Receptor Activity Is Associated With Downregulation of FK506-Binding Proteins Circulation, April 28, 2009; 119(16): 2179 - 2187. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. S. Dhalla, H. K. Saini-Chohan, D. Rodriguez-Leyva, V. Elimban, M. R. Dent, and P. S. Tappia Subcellular remodelling may induce cardiac dysfunction in congestive heart failure Cardiovasc Res, February 15, 2009; 81(3): 429 - 438. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Maczewski and U. Mackiewicz Effect of metoprolol and ivabradine on left ventricular remodelling and Ca2+ handling in the post-infarction rat heart Cardiovasc Res, July 1, 2008; 79(1): 42 - 51. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Yumino and T. D. Bradley Central Sleep Apnea and Cheyne-Stokes Respiration Proceedings of the ATS, February 15, 2008; 5(2): 226 - 236. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Yamamoto, M. Yano, X. Xu, H. Uchinoumi, H. Tateishi, M. Mochizuki, T. Oda, S. Kobayashi, N. Ikemoto, and M. Matsuzaki Identification of Target Domains of the Cardiac Ryanodine Receptor to Correct Channel Disorder in Failing Hearts Circulation, February 12, 2008; 117(6): 762 - 772. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Lehnart and A. R. Marks Regulation of Ryanodine Receptors in the Heart Circ. Res., October 12, 2007; 101(8): 746 - 749. [Full Text] [PDF]
|
|
|
|
 |
|
 T. Seidler, G. Hasenfuss, and L. S. Maier Targeting Altered Calcium Physiology in the Heart: Translational Approaches to Excitation, Contraction, and Transcription Physiology, October 1, 2007; 22(5): 328 - 334. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Chen-Izu, C. W. Ward, W. Stark Jr., T. Banyasz, M. P. Sumandea, C. W. Balke, L. T. Izu, and X. H. T. Wehrens Phosphorylation of RyR2 and shortening of RyR2 cluster spacing in spontaneously hypertensive rat with heart failure Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2409 - H2417. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Feng, D. B. Hoover, and N. Paolocci Forever Young?: Nerve Growth Factor, Sympathetic Fibers, and Right Ventricle Pressure Overload Circ. Res., June 22, 2007; 100(12): 1670 - 1672. [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Cheng, I. George, G.-H. Yi, S. Reiken, A. Gu, Y. K. Tao, J. Muraskin, S. Qin, K.-L. He, I. Hay, et al. Bradycardic Therapy Improves Left Ventricular Function and Remodeling in Dogs with Coronary Embolization-Induced Chronic Heart Failure J. Pharmacol. Exp. Ther., May 1, 2007; 321(2): 469 - 476. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. H. T. Wehrens, S. E. Lehnart, S. Reiken, J. A. Vest, A. Wronska, and A. R. Marks Inaugural Article: Ryanodine receptor/calcium release channel PKA phosphorylation: A critical mediator of heart failure progression PNAS, January 17, 2006; 103(3): 511 - 518. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. R. Sipido and D. Eisner Something old, something new: Changing views on the cellular mechanisms of heart failure Cardiovasc Res, November 1, 2005; 68(2): 167 - 174. [Full Text] [PDF]
|
|
|
|
|
|
J.-F. Wang, A. Meissner, S. Malek, Y. Chen, Q. Ke, J. Zhang, V. Chu, T. G. Hampton, C. S. Crumpacker, W. H. Abelmann, et al. Propranolol ameliorates and epinephrine exacerbates progression of acute and chronic viral myocarditis Am J Physiol Heart Circ Physiol, October 1, 2005; 289(4): H1577 - H1583. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Kontula, P. J. Laitinen, A. Lehtonen, L. Toivonen, M. Viitasalo, and H. Swan Catecholaminergic polymorphic ventricular tachycardia: Recent mechanistic insights Cardiovasc Res, August 15, 2005; 67(3): 379 - 387. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. R. Schwarz, R. Gupta, T. P. Diep, B. Nowak, S. Kostin, B. Grohmann, B. F. Uretsky, and J. Schaper Carvedilol Improves Myocardial Contractility Compared With Metoprolol in Patients With Chronic Hibernating Myocardium After Revascularization Journal of Cardiovascular Pharmacology and Therapeutics, July 1, 2005; 10(3): 181 - 190. [Abstract] [PDF]
|
|
|
|
|
|
S. E. Lehnart, X. H.T. Wehrens, and A. R. Marks Defective Ryanodine Receptor Interdomain Interactions May Contribute to Intracellular Ca2+ Leak: A Novel Therapeutic Target in Heart Failure Circulation, June 28, 2005; 111(25): 3342 - 3346. [Full Text] [PDF]
|
|
|
|
|
|
T. Oda, M. Yano, T. Yamamoto, T. Tokuhisa, S. Okuda, M. Doi, T. Ohkusa, Y. Ikeda, S. Kobayashi, N. Ikemoto, et al. Defective Regulation of Interdomain Interactions Within the Ryanodine Receptor Plays a Key Role in the Pathogenesis of Heart Failure Circulation, June 28, 2005; 111(25): 3400 - 3410. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Klotz, A. Barbone, S. Reiken, J. W. Holmes, Y. Naka, M. C. Oz, A. R. Marks, and D. Burkhoff Left ventricular assist device support normalizes left and right ventricular beta-adrenergic pathway properties J. Am. Coll. Cardiol., March 1, 2005; 45(5): 668 - 676. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Christ, P. Boknik, S. Wohrl, E. Wettwer, E.M. Graf, R.F. Bosch, M. Knaut, W. Schmitz, U. Ravens, and D. Dobrev L-Type Ca2+ Current Downregulation in Chronic Human Atrial Fibrillation Is Associated With Increased Activity of Protein Phosphatases Circulation, October 26, 2004; 110(17): 2651 - 2657. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. Farr and C. T. Basson Sparking the Failing Heart N. Engl. J. Med., July 8, 2004; 351(2): 185 - 187. [Full Text] [PDF]
|
|
|
|
|
|
S. E. Lehnart, X. H.T. Wehrens, P. J. Laitinen, S. R. Reiken, S.-X. Deng, Z. Cheng, D. W. Landry, K. Kontula, H. Swan, and A. R. Marks Sudden Death in Familial Polymorphic Ventricular Tachycardia Associated With Calcium Release Channel (Ryanodine Receptor) Leak Circulation, June 29, 2004; 109(25): 3208 - 3214. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Okuda, M. Yano, M. Doi, T. Oda, T. Tokuhisa, M. Kohno, S. Kobayashi, T. Yamamoto, T. Ohkusa, and M. Matsuzaki Valsartan Restores Sarcoplasmic Reticulum Function With No Appreciable Effect on Resting Cardiac Function in Pacing-Induced Heart Failure Circulation, February 24, 2004; 109(7): 911 - 919. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. M. Plank, A. Yatani, H. Ritsu, S. Witt, B. Glascock, M. J. Lalli, M. Periasamy, C. Fiset, N. Benkusky, H. H. Valdivia, et al. Calcium dynamics in the failing heart: restoration by {beta}-adrenergic receptor blockade Am J Physiol Heart Circ Physiol, June 5, 2003; 285(1): H305 - H315. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Reiken, X. H.T. Wehrens, J. A. Vest, A. Barbone, S. Klotz, D. Mancini, D. Burkhoff, and A. R. Marks {beta}-Blockers Restore Calcium Release Channel Function and Improve Cardiac Muscle Performance in Human Heart Failure Circulation, May 20, 2003; 107(19): 2459 - 2466. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M Scoote, P A Poole-Wilson, and A J Williams The therapeutic potential of new insights into myocardial excitation-contraction coupling Heart, April 1, 2003; 89(4): 371 - 376. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. R. Marks A Guide for the Perplexed: Towards an Understanding of the Molecular Basis of Heart Failure Circulation, March 25, 2003; 107(11): 1456 - 1459. [Full Text] [PDF]
|
|
|
|
 |
|
 S. Reiken, A. Lacampagne, H. Zhou, A. Kherani, S. E. Lehnart, C. Ward, F. Huang, M. Gaburjakova, J. Gaburjakova, N. Rosemblit, et al. PKA phosphorylation activates the calcium release channel (ryanodine receptor) in skeletal muscle: defective regulation in heart failure J. Cell Biol., March 17, 2003; 160(6): 919 - 928. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. R. Houser and K. B. Margulies Is Depressed Myocyte Contractility Centrally Involved in Heart Failure? Circ. Res., March 7, 2003; 92(4): 350 - 358. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. P. Schmitt, M. Kamisago, M. Asahi, G. H. Li, F. Ahmad, U. Mende, E. G. Kranias, D. H. MacLennan, J. G. Seidman, and C. E. Seidman Dilated Cardiomyopathy and Heart Failure Caused by a Mutation in Phospholamban Science, February 28, 2003; 299(5611): 1410 - 1413. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Hasenfuss and T. Seidler Treatment of Heart Failure Through Stabilization of the Cardiac Ryanodine Receptor Circulation, January 28, 2003; 107(3): 378 - 380. [Full Text] [PDF]
|
|
|
|
|
|
M. Yano, S. Kobayashi, M. Kohno, M. Doi, T. Tokuhisa, S. Okuda, M. Suetsugu, T. Hisaoka, M. Obayashi, T. Ohkusa, et al. FKBP12.6-Mediated Stabilization of Calcium-Release Channel (Ryanodine Receptor) as a Novel Therapeutic Strategy Against Heart Failure Circulation, January 28, 2003; 107(3): 477 - 484. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Reiken, M. Gaburjakova, S. Guatimosim, A. M. Gomez, J. D'Armiento, D. Burkhoff, J. Wang, G. Vassort, W. J. Lederer, and A. R. Marks Protein Kinase A Phosphorylation of the Cardiac Calcium Release Channel (Ryanodine Receptor) in Normal and Failing Hearts. ROLE OF PHOSPHATASES AND RESPONSE TO ISOPROTERENOL J. Biol. Chem., January 3, 2003; 278(1): 444 - 453. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Sjaastad, J A. Wasserstrom, and O. M Sejersted Heart failure - a challenge to our current concepts of excitation-contraction coupling J. Physiol., January 1, 2003; 546(1): 33 - 47. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Scoote and A. J Williams The cardiac ryanodine receptor (calcium release channel): Emerging role in heart failure and arrhythmia pathogenesis Cardiovasc Res, December 1, 2002; 56(3): 359 - 372. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D.A. Eisner and A.W. Trafford Heart Failure and the Ryanodine Receptor: Does Occam's Razor Rule? Circ. Res., November 29, 2002; 91(11): 979 - 981. [Full Text] [PDF]
|
|
|
|
|
|
A. R. Marks Clinical Implications of Cardiac Ryanodine Receptor/Calcium Release Channel Mutations Linked to Sudden Cardiac Death Circulation, July 2, 2002; 106(1): 8 - 10. [Full Text] [PDF]
|
|
|
|
|
|
M. Doi, M. Yano, S. Kobayashi, M. Kohno, T. Tokuhisa, S. Okuda, M. Suetsugu, Y. Hisamatsu, T. Ohkusa, M. Kohno, et al. Propranolol Prevents the Development of Heart Failure by Restoring FKBP12.6-Mediated Stabilization of Ryanodine Receptor Circulation, March 19, 2002; 105(11): 1374 - 1379. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. R. Marks, S. Reiken, and S. O. Marx Progression of Heart Failure: Is Protein Kinase A Hyperphosphorylation of the Ryanodine Receptor a Contributing Factor? Circulation, January 22, 2002; 105(3): 272 - 275. [Full Text] [PDF]
|
|
|
|
 |
|
 X.H.T. WEHRENS and A.R. MARKS Myocardial Disease in Failing Hearts: Defective Excitation-Contraction Coupling Cold Spring Harb Symp Quant Biol, January 1, 2002; 67(0): 533 - 542. [Abstract] [PDF]
|
|