Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

PNAS 102 (27): 9607-9612

Copyright © 2005 by the National Academy of Sciences.


MEDICAL SCIENCES

Enhancing calstabin binding to ryanodine receptors improves cardiac and skeletal muscle function in heart failure

Xander H. T. Wehrens*, Stephan E. Lehnart*, Steven Reiken*, Roel van der Nagel{dagger}, Raymond Morales*, Jie Sun{ddagger}, Zhenzhuang Cheng{ddagger}, Shi-Xiang Deng{ddagger}, Leon J. de Windt{dagger}, Donald W. Landry{ddagger}, and Andrew R. Marks*,{ddagger},§

Departments of *Physiology and Cellular Biophysics and {ddagger}Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032; and {dagger}Hubrecht Laboratory, Royal Netherlands Academy of Arts and Sciences, 3584CT, Utrecht, The Netherlands

Edited by Eric N. Olson, University of Texas Southwestern Medical Center, Dallas, TX

Accepted for publication April 20, 2005.

Received for publication January 14, 2005.

Abstract: Abnormalities in intracellular calcium release and reuptake are responsible for decreased contractility in heart failure (HF). We have previously shown that cardiac ryanodine receptors (RyRs) are protein kinase A-hyperphosphorylated and depleted of the regulatory subunit calstabin-2 in HF. Moreover, similar alterations in skeletal muscle RyR have been linked to increased fatigability in HF. To determine whether restoration of calstabin binding to RyR may ameliorate cardiac and skeletal muscle dysfunction in HF, we treated WT and calstabin-2-/- mice subjected to myocardial infarction (MI) with JTV519. JTV519, a 1,4-benzothiazepine, is a member of a class of drugs known as calcium channel stabilizers, previously shown to increase calstabin binding to RyR. Echocardiography at 21 days after MI demonstrated a significant increase in ejection fraction in WT mice treated with JTV519 (45.8 ± 5.1%) compared with placebo (31.1 ± 3.1%; P < 0.05). Coimmunoprecipitation experiments revealed increased amounts of calstabin-2 bound to the RyR2 channel in JTV519-treated WT mice. However, JTV519 did not show any of these beneficial effects in calstabin-2-/- mice with MI. Additionally, JTV519 improved skeletal muscle fatigue in WT and calstabin-2-/- mice with HF by increasing the binding of calstabin-1 to RyR1. The observation that treatment with JTV519 improved cardiac function in WT but not calstabin-2-/- mice indicates that calstabin-2 binding to RyR2 is required for the beneficial effects in failing hearts. We conclude that JTV519 may provide a specific way to treat the cardiac and skeletal muscle myopathy in HF by increasing calstabin binding to RyR.

Key Words: calcium • FKBP12.6 • myocardial infarction • contractility


Author contributions: X.H.T.W. and A.R.M. designed research; X.H.T.W., S.E.L., S.R., R.v.d.N., R.M., and J.S. performed research; X.H.T.W., S.E.L., R.v.d.N., Z.C., S.-X.D., L.J.d.W., and D.W.L. contributed new reagents/analytic tools; X.H.T.W., S.E.L., S.R., R.M., and A.R.M. analyzed data; and X.H.T.W. and A.R.M. wrote the paper.

This paper was submitted directly (Track II) to the PNAS office.

Abbreviations: PKA, protein kinase A; RyR, ryanodine receptor; HF, heart failure; SR, sarcoplasmic reticulum; SERCA, SR calcium ATPase; MI, myocardial infarction.

§ To whom correspondence should be addressed at: Department of Physiology and Cellular Biophysics, Center for Molecular Cardiology, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, P&S Box 9-401, New York, NY 10032. E-mail: arm42{at}columbia.edu.

© 2005 by The National Academy of Sciences of the USA


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Role of RyR2 Phosphorylation in Heart Failure and Arrhythmias: Protein Kinase A-Mediated Hyperphosphorylation of the Ryanodine Receptor at Serine 2808 Does Not Alter Cardiac Contractility or Cause Heart Failure and Arrhythmias.
S. R. Houser (2014)
Circ. Res. 114, 1320-1327
   Abstract »    Full Text »    PDF »
Cardiac Myocyte Z-Line Calmodulin Is Mainly RyR2-Bound, and Reduction Is Arrhythmogenic and Occurs in Heart Failure.
Y. Yang, T. Guo, T. Oda, A. Chakraborty, L. Chen, H. Uchinoumi, A. A. Knowlton, B. R. Fruen, R. L. Cornea, G. Meissner, et al. (2014)
Circ. Res. 114, 295-306
   Abstract »    Full Text »    PDF »
Abnormal Calcium Cycling and Cardiac Arrhythmias Associated With the Human Ser96Ala Genetic Variant of Histidine-Rich Calcium-Binding Protein.
V. P. Singh, J. Rubinstein, D. A. Arvanitis, X. Ren, X. Gao, K. Haghighi, M. Gilbert, V. R. Iyer, D. H. Kim, C. Cho, et al. (2013)
JAHA 2, e000460
   Abstract »    Full Text »    PDF »
Calcium Leak Through Ryanodine Receptors Leads to Atrial Fibrillation in 3 Mouse Models of Catecholaminergic Polymorphic Ventricular Tachycardia.
J. Shan, W. Xie, M. Betzenhauser, S. Reiken, B.-X. Chen, A. Wronska, and A. R. Marks (2012)
Circ. Res. 111, 708-717
   Abstract »    Full Text »    PDF »
Designing Calcium Release Channel Inhibitors with Enhanced Electron Donor Properties: Stabilizing the Closed State of Ryanodine Receptor Type 1.
Y. Ye, D. Yaeger, L. J. Owen, J. O. Escobedo, J. Wang, J. D. Singer, R. M. Strongin, and J. J. Abramson (2012)
Mol. Pharmacol. 81, 53-62
   Abstract »    Full Text »    PDF »
Upregulation of the CaV 1.1-ryanodine receptor complex in a rat model of critical illness myopathy.
S. D. Kraner, Q. Wang, K. R. Novak, D. Cheng, D. R. Cool, J. Peng, and M. M. Rich (2011)
Am J Physiol Regulatory Integrative Comp Physiol 300, R1384-R1391
   Abstract »    Full Text »    PDF »
Endoplasmic-Reticulum Calcium Depletion and Disease.
D. Mekahli, G. Bultynck, J. B. Parys, H. De Smedt, and L. Missiaen (2011)
Cold Spring Harb Perspect Biol 3, a004317
   Abstract »    Full Text »    PDF »
CGP-37157 Inhibits the Sarcoplasmic Reticulum Ca2+ ATPase and Activates Ryanodine Receptor Channels in Striated Muscle.
J. T. Neumann, P. L. Diaz-Sylvester, S. Fleischer, and J. A. Copello (2011)
Mol. Pharmacol. 79, 141-147
   Abstract »    Full Text »    PDF »
Increasing Cardiac Contractility After Myocardial Infarction Exacerbates Cardiac Injury and Pump Dysfunction.
H. Zhang, X. Chen, E. Gao, S. M. MacDonnell, W. Wang, M. Kolpakov, H. Nakayama, X. Zhang, N. Jaleel, D. M. Harris, et al. (2010)
Circ. Res. 107, 800-809
   Abstract »    Full Text »    PDF »
Leaky RyR2 trigger ventricular arrhythmias in Duchenne muscular dystrophy.
J. Fauconnier, J. Thireau, S. Reiken, C. Cassan, S. Richard, S. Matecki, A. R. Marks, and A. Lacampagne (2010)
PNAS 107, 1559-1564
   Abstract »    Full Text »    PDF »
Alteration of sarcoplasmic reticulum Ca2+ release termination by ryanodine receptor sensitization and in heart failure.
T. L. Domeier, L. A. Blatter, and A. V. Zima (2009)
J. Physiol. 587, 5197-5209
   Abstract »    Full Text »    PDF »
Remodeling of ryanodine receptor complex causes "leaky" channels: A molecular mechanism for decreased exercise capacity.
A. M. Bellinger, S. Reiken, M. Dura, P. W. Murphy, S.-X. Deng, D. W. Landry, D. Nieman, S. E. Lehnart, M. Samaru, A. LaCampagne, et al. (2008)
PNAS 105, 2198-2202
   Abstract »    Full Text »    PDF »
Skeletal Muscle Fatigue: Cellular Mechanisms.
D. G. Allen, G. D. Lamb, and H. Westerblad (2008)
Physiol Rev 88, 287-332
   Abstract »    Full Text »    PDF »
Inhibition of SR Ca2+ uptake: A novel action of the RyR2-FKBP12.6 antagonist K201.
A. F. James (2007)
Cardiovasc Res 76, 199-201
   Full Text »    PDF »
K201 modulates excitation-contraction coupling and spontaneous Ca2+ release in normal adult rabbit ventricular cardiomyocytes.
C.M. Loughrey, N. Otani, T. Seidler, M.A. Craig, R. Matsuda, N. Kaneko, and G.L. Smith (2007)
Cardiovasc Res 76, 236-246
   Abstract »    Full Text »    PDF »
Phosphorylation of RyR2 and shortening of RyR2 cluster spacing in spontaneously hypertensive rat with heart failure.
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 (2007)
Am J Physiol Heart Circ Physiol 293, H2409-H2417
   Abstract »    Full Text »    PDF »
Acute beta-Adrenergic Overload Produces Myocyte Damage through Calcium Leakage from the Ryanodine Receptor 2 but Spares Cardiac Stem Cells.
G. M. Ellison, D. Torella, I. Karakikes, S. Purushothaman, A. Curcio, C. Gasparri, C. Indolfi, N. T. Cable, D. F. Goldspink, and B. Nadal-Ginard (2007)
J. Biol. Chem. 282, 11397-11409
   Abstract »    Full Text »    PDF »
Arrhythmogenic Ion-Channel Remodeling in the Heart: Heart Failure, Myocardial Infarction, and Atrial Fibrillation.
S. Nattel, A. Maguy, S. Le Bouter, and Y.-H. Yeh (2007)
Physiol Rev 87, 425-456
   Abstract »    Full Text »    PDF »
Calcium and Arrhythmogenesis.
H. E. D. J. ter Keurs and P. A. Boyden (2007)
Physiol Rev 87, 457-506
   Abstract »    Full Text »    PDF »
Profile of Andrew R. Marks.
P. Downey (2006)
PNAS 103, 8915-8917
   Full Text »    PDF »
Stabilization of cardiac ryanodine receptor prevents intracellular calcium leak and arrhythmias.
S. E. Lehnart, C. Terrenoire, S. Reiken, X. H. T. Wehrens, L.-S. Song, E. J. Tillman, S. Mancarella, J. Coromilas, W. J. Lederer, R. S. Kass, et al. (2006)
PNAS 103, 7906-7910
   Abstract »    Full Text »    PDF »
Analysis of calstabin2 (FKBP12.6)-ryanodine receptor interactions: Rescue of heart failure by calstabin2 in mice.
F. Huang, J. Shan, S. Reiken, X. H. T. Wehrens, and A. R. Marks (2006)
PNAS 103, 3456-3461
   Abstract »    Full Text »    PDF »
A mutation in the human phospholamban gene, deleting arginine 14, results in lethal, hereditary cardiomyopathy.
K. Haghighi, F. Kolokathis, A. O. Gramolini, J. R. Waggoner, L. Pater, R. A. Lynch, G.-C. Fan, D. Tsiapras, R. R. Parekh, G. W. Dorn II, et al. (2006)
PNAS 103, 1388-1393
   Abstract »    Full Text »    PDF »
Ryanodine receptor/calcium release channel PKA phosphorylation: A critical mediator of heart failure progression.
X. H. T. Wehrens, S. E. Lehnart, S. Reiken, J. A. Vest, A. Wronska, and A. R. Marks (2006)
PNAS 103, 511-518
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882