© 2000 American Heart Association, Inc.
Review |
Calcineurin and Beyond
Cardiac Hypertrophic Signaling
From the Department of Pediatrics, University of Cincinnati, Division of Molecular Cardiovascular Biology, Children’s Hospital Medical Center, Cincinnati, Ohio.
Correspondence to Jeffery D. Molkentin, PhD, Division of Molecular Cardiovascular Biology, Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229-3039. E-mail molkj0{at}chmcc.org\\ © 2000 American Heart Association, Inc.
Abstract—In response to increased ventricular wall tension or neurohumoral stimuli, the myocardium undergoes an adaptive hypertrophy response that temporarily augments pump function. Although initially beneficial, sustained cardiac hypertrophy can lead to decompensation and cardiomyopathy. Recent studies have focused on characterizing the molecular mechanisms that underlie cardiac hypertrophy. An increasing number of signal transduction pathways have been identified as important regulators of the hypertrophic response, including the low–molecular weight GTPases (Ras, RhoA, and Rac), mitogen-activated protein kinases, protein kinase C, and calcineurin. This review will discuss an emerging body of evidence that implicates the calcium-calmodulin–activated protein phosphatase calcineurin as a physiological regulator of the cardiac hypertrophic response. Although the sufficiency of calcineurin to promote cardiomyocyte hypertrophy in vivo and in vitro is established, its overall necessity as a hypertrophic mediator is currently an area of ongoing debate. The use of the calcineurin-inhibitory agents cyclosporine A and FK506 have suggested a necessary role for calcineurin in many, but not all, animal models of hypertrophy or cardiomyopathy. The evidence implicating a role for calcineurin signaling in the heart will be weighed against a growing body of literature suggesting necessary roles for a diverse array of intracellular signaling pathways, highlighting the multifactorial nature of the hypertrophic program.
Key Words: calcineurin • cardiac hypertrophy • transcription • heart failure • signaling
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|
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|
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|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
S. E. Hardt and J. Sadoshima Glycogen Synthase Kinase-3{beta}: A Novel Regulator of Cardiac Hypertrophy and Development Circ. Res., May 31, 2002; 90(10): 1055 - 1063. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. J Wilkins and J. D Molkentin Calcineurin and cardiac hypertrophy: Where have we been? Where are we going? J. Physiol., May 15, 2002; 541(1): 1 - 8. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
G. Chu, A. N. Carr, K. B. Young, J.W. Lester, A. Yatani, A. Sanbe, M. C. Colbert, S. M. Schwartz, K. F. Frank, P. D. Lampe, et al. Enhanced myocyte contractility and Ca2+ handling in a calcineurin transgenic model of heart failure Cardiovasc Res, April 1, 2002; 54(1): 105 - 116. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. FAUVEL, P. MARCHETTI, G. OBERT, O. JOULAIN, C. CHOPIN, P. FORMSTECHER, and R. NEVIERE Protective Effects of Cyclosporin A from Endotoxin-induced Myocardial Dysfunction and Apoptosis in Rats Am. J. Respir. Crit. Care Med., February 15, 2002; 165(4): 449 - 455. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Mendez and M. C. LaPointe Trophic Effects of the Cyclooxygenase-2 Product Prostaglandin E2 in Cardiac Myocytes Hypertension, February 1, 2002; 39(2): 382 - 388. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. L. Antos, T. A. McKinsey, N. Frey, W. Kutschke, J. McAnally, J. M. Shelton, J. A. Richardson, J. A. Hill, and E. N. Olson Activated glycogen synthase-3beta suppresses cardiac hypertrophy in vivo PNAS, January 7, 2002; (2002) 231619298. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Wang, W. Kutschke, K. E. Richardson, M. Karimi, and J. A. Hill Electrical Remodeling in Pressure-Overload Cardiac Hypertrophy: Role of Calcineurin Circulation, October 2, 2001; 104(14): 1657 - 1663. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D.-S. Lim, R. Roberts, and A. J. Marian Expression profiling of cardiac genes in human hypertrophic cardiomyopathy: insight into the pathogenesis of phenotypes J. Am. Coll. Cardiol., October 1, 2001; 38(4): 1175 - 1180. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. W. Dorn II Calcineurin Inhibition in Hypertrophy : Back From the Dead! Circulation, July 3, 2001; 104(1): 9 - 11. [Full Text] [PDF]
|
|
|
|
|
|
T. E Hebert Signalling in cardiac disease: the molecular deficit at the heart of the problem Cardiovasc Res, April 1, 2001; 50(1): 7 - 9. [Full Text] [PDF]
|
|
|
|
|
|
H. W. Lim, L. New, J. Han, and J. D. Molkentin Calcineurin Enhances MAPK Phosphatase-1 Expression and p38 MAPK Inactivation in Cardiac Myocytes J. Biol. Chem., May 4, 2001; 276(19): 15913 - 15919. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Wang, B. Nolan, W. Kutschke, and J. A. Hill Na+-Ca2+ Exchanger Remodeling in Pressure Overload Cardiac Hypertrophy J. Biol. Chem., May 18, 2001; 276(21): 17706 - 17711. [Abstract] [Full Text] [PDF]
|
|
|
|
|
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|
|
|
|
|
|
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|
|