Published online before print March 4, 2002, doi: 10.1161/hc1102.105270
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2002;105:1374.)
© 2002 American Heart Association, Inc.
Basic Science Reports |
Propranolol Prevents the Development of Heart Failure by Restoring FKBP12.6-Mediated Stabilization of Ryanodine Receptor
From the Department of Medical Bioregulation, Division of Cardiovascular Medicine, Yamaguchi University School of Medicine, Yamaguchi, Japan.
Correspondence to Masunori Matsuzaki, MD, PhD, Department of Internal Medicine, Yamaguchi University School of Medicine, 1-1-1 Minamikogushi, Ube, Yamaguchi, 755-8505, Japan. E-mail masunori{at}po.cc.yamaguchi-u.ac.jp
Background— In heart failure, protein kinase A-mediated hyperphosphorylation of ryanodine receptors (RyRs) in sarcoplasmic reticulum (SR) causes dissociation of FKBP12.6 from RyRs. This results in an abnormal Ca2+ leak through RyRs, possibly leading to cardiac dysfunction. In the present study, we assess whether ß-blockers can correct this defect in RyR in tachycardia-induced heart failure and thereby improve cardiac function.
Methods and Results— SRs were isolated from dog left ventricular muscles (normal group, 4 weeks of rapid right ventricular pacing with or without propranolol [P(+) or P(-)]). End-diastolic and end-systolic diameters both increased less in P(+) than P(-), associated with a smaller decrease in fractional shortening in P(+). In SR from P(-), a prominent Ca2+ leak was observed, and FK506 (which dissociates FKBP12.6 from RyR) did not induce an additional Ca2+ leak. However, there was no appreciable Ca2+ leak in SR from P(+), although FK506 induced a Ca2+ leak as in normal SRs. In SR from P(+), an FK506-induced conformational change in RyR, which was virtually absent in SR from P(-), was observed as in normal SRs. Both the stoichiometry of FKBP12.6 versus RyR, assessed by [3H]FK506 and [3H]ryanodine binding assays, and the protein expression of FKBP12.6, assessed by Western blot analysis, were restored by propranolol toward the levels seen in normal SRs.
Conclusions— Low-dose propranolol corrects the defective interaction of FKBP12.6 with RyR (restoration of RyR conformational change and prevention of Ca2+ leak from RyR), apparently resulting in an attenuation of intracellular Ca2+ overload and hence preventing the development of left ventricular remodeling in heart failure.
Key Words: ß-blocker • heart failure • sarcoplasmic reticulum • calcium
This article has been cited by other articles:
 |
|
 |
|
  J. R. H. Mauban, M. O'Donnell, S. Warrier, S. Manni, and M. Bond AKAP-Scaffolding Proteins and Regulation of Cardiac Physiology Physiology, April 1, 2009; 24(2): 78 - 87. [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]
|
|
|
|
 |
|
 C. H. George Sarcoplasmic reticulum Ca2+ leak in heart failure: mere observation or functional relevance? Cardiovasc Res, January 15, 2008; 77(2): 302 - 314. [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]
|
|
|
|
 |
|
 L. Groban and J. Butterworth Perioperative management of chronic heart failure. Anesth. Analg., September 1, 2006; 103(3): 557 - 575. [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]
|
|
|
|
|
|
C. H. George, H. Jundi, N. Walters, N. L. Thomas, R. R. West, and F. A. Lai Arrhythmogenic Mutation-Linked Defects in Ryanodine Receptor Autoregulation Reveal a Novel Mechanism of Ca2+ Release Channel Dysfunction Circ. Res., January 6, 2006; 98(1): 88 - 97. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Yano, S. Okuda, T. Oda, T. Tokuhisa, H. Tateishi, M. Mochizuki, T. Noma, M. Doi, S. Kobayashi, T. Yamamoto, et al. Correction of Defective Interdomain Interaction Within Ryanodine Receptor by Antioxidant Is a New Therapeutic Strategy Against Heart Failure Circulation, December 6, 2005; 112(23): 3633 - 3643. [Abstract] [Full Text] [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]
|
|
|
|
|
|
J. A. Vest, X. H.T. Wehrens, S. R. Reiken, S. E. Lehnart, D. Dobrev, P. Chandra, P. Danilo, U. Ravens, M. R. Rosen, and A. R. Marks Defective Cardiac Ryanodine Receptor Regulation During Atrial Fibrillation Circulation, April 26, 2005; 111(16): 2025 - 2032. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Zissimopoulos and F. A. Lai Interaction of FKBP12.6 with the Cardiac Ryanodine Receptor C-terminal Domain J. Biol. Chem., February 18, 2005; 280(7): 5475 - 5485. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. A. Kass, J. G.F. Bronzwaer, and W. J. Paulus What Mechanisms Underlie Diastolic Dysfunction in Heart Failure? Circ. Res., June 25, 2004; 94(12): 1533 - 1542. [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]
|
|
|
|
 |
|
 T. Zhang, S. Miyamoto, and J. H. Brown Cardiomyocyte Calcium and Calcium/Calmodulin-dependent Protein Kinase II: Friends or Foes? Recent Prog. Horm. Res., January 1, 2004; 59(1): 141 - 168. [Abstract] [Full Text]
|
|
|
|
|
|
C. H. George, G. V. Higgs, and F. A. Lai Ryanodine Receptor Mutations Associated With Stress-Induced Ventricular Tachycardia Mediate Increased Calcium Release in Stimulated Cardiomyocytes Circ. Res., September 19, 2003; 93(6): 531 - 540. [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]
|
|
|
|
|
|
H. Masumiya, R. Wang, J. Zhang, B. Xiao, and S. R. W. Chen Localization of the 12.6-kDa FK506-binding Protein (FKBP12.6) Binding Site to the NH2-terminal Domain of the Cardiac Ca2+ Release Channel (Ryanodine Receptor) J. Biol. Chem., January 31, 2003; 278(6): 3786 - 3792. [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]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 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]
|
|