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Science 11 September 1998:
Vol. 281. no. 5383, pp. 1690 - 1693
DOI: 10.1126/science.281.5383.1690
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Reports

Prevention of Cardiac Hypertrophy in Mice by Calcineurin Inhibition

Mark A. Sussman, Hae W. Lim, Natalie Gude, Tyler Taigen, Eric N. Olson, Jeffrey Robbins, Melissa C. Colbert, Antonio Gualberto, David F. Wieczorek, Jeffery D. Molkentin *

Hypertrophic cardiomyopathy (HCM) is an inherited form of heart disease that affects 1 in 500 individuals. Here it is shown that calcineurin, a calcium-regulated phosphatase, plays a critical role in the pathogenesis of HCM. Administration of the calcineurin inhibitors cyclosporin and FK506 prevented disease in mice that were genetically predisposed to develop HCM as a result of aberrant expression of tropomodulin, myosin light chain-2, or fetal beta -tropomyosin in the heart. Cyclosporin had a similar effect in a rat model of pressure-overload hypertrophy. These results suggest that calcineurin inhibitors merit investigation as potential therapeutics for certain forms of human heart disease.

M. A. Sussman, H. W. Lim, N. Gude, T. Taigen, J. Robbins, M. C. Colbert, J. D. Molkentin, Division of Molecular Cardiovascular Biology, Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA. E. N. Olson, Department of Molecular Biology and Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA. A. Gualberto, Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA. D. F. Wieczorek, Department of Molecular Genetics, University of Cincinnati, Cincinnati, OH 45267, USA.
*   To whom correspondence should be addressed. E-mail: molkj0{at}chmcc.org

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   Abstract »    Full Text »    PDF »
Cardiac Hypertrophy Is Not a Required Compensatory Response to Short-Term Pressure Overload.
J. A. Hill, M. Karimi, W. Kutschke, R. L. Davisson, K. Zimmerman, Z. Wang, R. E. Kerber, and R. M. Weiss (2000)
Circulation 101, 2863-2869
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Cardiotrophic Effects of Protein Kinase C {epsilon} : Analysis by In Vivo Modulation of PKC{epsilon} Translocation.
D. Mochly-Rosen, G. Wu, H. Hahn, H. Osinska, T. Liron, J. N. Lorenz, A. Yatani, J. Robbins, and G. W. Dorn II (2000)
Circ. Res. 86, 1173-1179
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COMPARISON OF THE EFFECTS OF FETAL CARDIOMYOCYTE AND SKELETAL MYOBLAST TRANSPLANTATION ON POSTINFARCTION LEFT VENTRICULAR FUNCTION.
M. Scorsin, A. Hagege, J.-T. Vilquin, M. Fiszman, F. Marotte, J.-L. Samuel, L. Rappaport, K. Schwartz, and P. Menasche (2000)
J. Thorac. Cardiovasc. Surg. 119, 1169-1175
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Cyclosporin A inhibits cardiac hypertrophy and enhances cardiac dysfunction during postinfarction failure in rats.
E. Oie, R. Bjornerheim, O. P. F. Clausen, and H. Attramadal (2000)
Am J Physiol Heart Circ Physiol 278, H2115-H2123
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Calcineurin Expression, Activation, and Function in Cardiac Pressure-Overload Hypertrophy.
H. W. Lim, L. J. De Windt, L. Steinberg, T. Taigen, S. A. Witt, T. R. Kimball, and J. D. Molkentin (2000)
Circulation 101, 2431-2437
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Ca2+/Calmodulin-dependent Kinase II and Calcineurin Play Critical Roles in Endothelin-1-induced Cardiomyocyte Hypertrophy.
W. Zhu, Y. Zou, I. Shiojima, S. Kudoh, R. Aikawa, D. Hayashi, M. Mizukami, H. Toko, F. Shibasaki, Y. Yazaki, et al. (2000)
J. Biol. Chem. 275, 15239-15245
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Calcineurin Is Activated in Rat Hearts With Physiological Left Ventricular Hypertrophy Induced by Voluntary Exercise Training.
Y. Eto, K. Yonekura, M. Sonoda, N. Arai, M. Sata, S. Sugiura, K. Takenaka, A. Gualberto, M. L. Hixon, M. W. Wagner, et al. (2000)
Circulation 101, 2134-2137
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Calcineurin Promotes Protein Kinase C and c-Jun NH2-terminal Kinase Activation in the Heart. CROSS-TALK BETWEEN CARDIAC HYPERTROPHIC SIGNALING PATHWAYS.
L. J. De Windt, H. W. Lim, S. Haq, T. Force, and J. D. Molkentin (2000)
J. Biol. Chem. 275, 13571-13579
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Conditional expression of a Gi-coupled receptor causes ventricular conduction delay and a lethal cardiomyopathy.
C. H. Redfern, M. Y. Degtyarev, A. T. Kwa, N. Salomonis, N. Cotte, T. Nanevicz, N. Fidelman, K. Desai, K. Vranizan, E. K. Lee, et al. (2000)
PNAS 97, 4826-4831
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Hypertrophy and dilation: a TOTally new story?.
S. Baudet (2000)
Cardiovasc Res 46, 17-19
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Hypertrophic defect unmasked by calcineurin expression in asymptomatic tropomodulin overexpressing transgenic mice.
M. A. Sussman, S. Welch, A. Walker, R. Klevitsky, T. E. Hewett, S. A. Witt, T. R. Kimball, R. Price, H. W. Lim, and J. D. Molkentin (2000)
Cardiovasc Res 46, 90-101
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A Protein Encoded within the Down Syndrome Critical Region Is Enriched in Striated Muscles and Inhibits Calcineurin Signaling.
B. Rothermel, R. B. Vega, J. Yang, H. Wu, R. Bassel-Duby, and R. S. Williams (2000)
J. Biol. Chem. 275, 8719-8725
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Targeted inhibition of calcineurin prevents agonist-induced cardiomyocyte hypertrophy.
T. Taigen, L. J. De Windt, H. W. Lim, and J. D. Molkentin (2000)
PNAS 97, 1196-1201
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Metabolic aspects of programmed cell survival and cell death in the heart.
C. Depre and H. Taegtmeyer (2000)
Cardiovasc Res 45, 538-548
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Electrical Stimulation of Neonatal Cardiac Myocytes Activates the NFAT3 and GATA4 Pathways and Up-regulates the Adenylosuccinate Synthetase 1 Gene.
Y. Xia, J. B. McMillin, A. Lewis, M. Moore, W. G. Zhu, R. S. Williams, and R. E. Kellems (2000)
J. Biol. Chem. 275, 1855-1863
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Effects of Serine/Threonine Protein Phosphatases on Ion Channels in Excitable Membranes.
S. Herzig and J. Neumann (2000)
Physiol Rev 80, 173-210
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Interleukin-1{beta} Regulates the Human Brain Natriuretic Peptide Promoter via Ca2+-Dependent Protein Kinase Pathways.
Q. He and M. C. LaPointe (2000)
Hypertension 35, 292-296
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Cyclosporin A Protects Against Angiotensin II-Induced End-Organ Damage in Double Transgenic Rats Harboring Human Renin and Angiotensinogen Genes.
E. Mervaala, D. N. Muller, J.-K. Park, R. Dechend, F. Schmidt, A. Fiebeler, M. Bieringer, V. Breu, D. Ganten, H. Haller, et al. (2000)
Hypertension 35, 360-366
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