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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

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