Circulation Research. 2004;94:110-118
Published online before print December 1, 2003, doi: 10.1161/01.RES.0000109415.17511.18
Published online before print December 1, 2003, doi: 10.1161/01.RES.0000109415.17511.18
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© 2004 American Heart Association, Inc.
Integrative Physiology |
Calcineurin/NFAT Coupling Participates in Pathological, but not Physiological, Cardiac Hypertrophy
From the Divisions of Molecular Cardiovascular Biology (B.J.W., Y.-S.D., O.F.B., S.A.P., J.X., D.M.P., J.D.M.) and Cardiology (F.J., T.R.K.), Department of Pediatrics, Children’s Hospital Medical Center, Cincinnati, Ohio.
Correspondence to Jeffery D. Molkentin, Division of Molecular Cardiovascular Biology, Department of Pediatrics, Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229-3039. E-mail jeff.molkentin{at}cchmc.org
Calcineurin (PP2B) is a calcium/calmodulin-activated, serine-threonine phosphatase that transmits signals to the nucleus through the dephosphorylation and translocation of nuclear factor of activated T cell (NFAT) transcription factors. Whereas calcineurin-NFAT signaling has been implicated in regulating the hypertrophic growth of the myocardium, considerable controversy persists as to its role in maintaining versus initiating hypertrophy, its role in pathological versus physiological hypertrophy, and its role in heart failure. To address these issues, NFAT-luciferase reporter transgenic mice were generated and characterized. These mice showed robust and calcineurin-specific activation in the heart that was inhibited with cyclosporin A. In the adult heart, NFAT-luciferase activity was upregulated in a delayed, but sustained manner throughout eight weeks of pathological cardiac hypertrophy induced by pressure-overload, or more dramatically following myocardial infarction-induced heart failure. In contrast, physiological hypertrophy as produced in two separate models of exercise training failed to show significant calcineurin-NFAT coupling in the heart at multiple time points, despite measurable increases in heart to body weight ratios. Moreover, stimulation of hypertrophy with growth hormone–insulin-like growth factor-1 (GH-IGF-1) failed to activate calcineurin-NFAT signaling in the heart or in culture, despite hypertrophy, activation of Akt, and activation of p70 S6K. Calcineurin Aß gene–targeted mice also showed a normal hypertrophic response after GH-IGF-1 infusion. Lastly, exercise- or GH-IGF-1–induced cardiac growth failed to show induction of hypertrophic marker gene expression compared with pressure-overloaded animals. Although a direct cause-and-effect relationship between NFAT-luciferase activity and pathological hypertrophy was not proven here, our results support the hypothesis that separable signaling pathways regulate pathological versus physiological hypertrophic growth of the myocardium, with calcineurin-NFAT potentially serving a regulatory role that is more specialized for maladaptive hypertrophy and heart failure.
Key Words: signaling • calcineurin • hypertrophy • heart failure • transcription
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A. Sotiropoulos, M. Ohanna, C. Kedzia, R. K. Menon, J. J. Kopchick, P. A. Kelly, and M. Pende Growth hormone promotes skeletal muscle cell fusion independent of insulin-like growth factor 1 up-regulation PNAS, May 9, 2006; 103(19): 7315 - 7320. [Abstract] [Full Text] [PDF]
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K. Walsh Akt Signaling and Growth of the Heart Circulation, May 2, 2006; 113(17): 2032 - 2034. [Full Text] [PDF]
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B. DeBosch, I. Treskov, T. S. Lupu, C. Weinheimer, A. Kovacs, M. Courtois, and A. J. Muslin Akt1 Is Required for Physiological Cardiac Growth Circulation, May 2, 2006; 113(17): 2097 - 2104. [Abstract] [Full Text] [PDF]
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J. Xu, N. L. Gong, I. Bodi, B. J. Aronow, P. H. Backx, and J. D. Molkentin Myocyte Enhancer Factors 2A and 2C Induce Dilated Cardiomyopathy in Transgenic Mice J. Biol. Chem., April 7, 2006; 281(14): 9152 - 9162. [Abstract] [Full Text] [PDF]
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T. Oka, M. Maillet, A. J. Watt, R. J. Schwartz, B. J. Aronow, S. A. Duncan, and J. D. Molkentin Cardiac-Specific Deletion of Gata4 Reveals Its Requirement for Hypertrophy, Compensation, and Myocyte Viability Circ. Res., March 31, 2006; 98(6): 837 - 845. [Abstract] [Full Text] [PDF]
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E. M. McNally Hypertrophic Cardiomyopathy: Exercise and Eat Right Circ. Res., March 3, 2006; 98(4): 443 - 445. [Full Text] [PDF]
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J. P. Konhilas, P. A. Watson, A. Maass, D. M. Boucek, T. Horn, B. L. Stauffer, S. W. Luckey, P. Rosenberg, and L. A. Leinwand Exercise Can Prevent and Reverse the Severity of Hypertrophic Cardiomyopathy Circ. Res., March 3, 2006; 98(4): 540 - 548. [Abstract] [Full Text] [PDF]
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J. Xu, T. R. Kimball, J. N. Lorenz, D. A. Brown, A. R. Bauskin, R. Klevitsky, T. E. Hewett, S. N. Breit, and J. D. Molkentin GDF15/MIC-1 Functions As a Protective and Antihypertrophic Factor Released From the Myocardium in Association With SMAD Protein Activation Circ. Res., February 17, 2006; 98(3): 342 - 350. [Abstract] [Full Text] [PDF]
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P. Uhlén, P. M. Burch, C. I. Zito, M. Estrada, B. E. Ehrlich, and A. M. Bennett Gain-of-function/Noonan syndrome SHP-2/Ptpn11 mutants enhance calcium oscillations and impair NFAT signaling PNAS, February 14, 2006; 103(7): 2160 - 2165. [Abstract] [Full Text] [PDF]
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B. R. Ertz-Berger, H. He, C. Dowell, S. M. Factor, T. E. Haim, S. Nunez, S. D. Schwartz, J. S. Ingwall, and J. C. Tardiff Changes in the chemical and dynamic properties of cardiac troponin T cause discrete cardiomyopathies in transgenic mice PNAS, December 13, 2005; 102(50): 18219 - 18224. [Abstract] [Full Text] [PDF]
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B. A. Rothermel, K. Berenji, P. Tannous, W. Kutschke, A. Dey, B. Nolan, K.-D. Yoo, E. Demetroulis, M. Gimbel, B. Cabuay, et al. Differential activation of stress-response signaling in load-induced cardiac hypertrophy and failure Physiol Genomics, September 21, 2005; 23(1): 18 - 27. [Abstract] [Full Text] [PDF]
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T. Oka, Y.-S. Dai, and J. D. Molkentin Regulation of Calcineurin through Transcriptional Induction of the calcineurin A{beta} Promoter In Vitro and In Vivo Mol. Cell. Biol., August 1, 2005; 25(15): 6649 - 6659. [Abstract] [Full Text] [PDF]
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L. V. G. Bosc, J. J. Layne, M. T. Nelson, and D. C. Hill-Eubanks Nuclear Factor of Activated T Cells and Serum Response Factor Cooperatively Regulate the Activity of an {alpha}-Actin Intronic Enhancer J. Biol. Chem., July 15, 2005; 280(28): 26113 - 26120. [Abstract] [Full Text] [PDF]
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K. Berenji, M. H. Drazner, B. A. Rothermel, and J. A. Hill Does load-induced ventricular hypertrophy progress to systolic heart failure? Am J Physiol Heart Circ Physiol, July 1, 2005; 289(1): H8 - H16. [Abstract] [Full Text] [PDF]
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J. P. Konhilas, U. Widegren, D. L. Allen, A. C. Paul, A. Cleary, and L. A. Leinwand Loaded wheel running and muscle adaptation in the mouse Am J Physiol Heart Circ Physiol, July 1, 2005; 289(1): H455 - H465. [Abstract] [Full Text] [PDF]
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C. Skurk, Y. Izumiya, H. Maatz, P. Razeghi, I. Shiojima, M. Sandri, K. Sato, L. Zeng, S. Schiekofer, D. Pimentel, et al. The FOXO3a Transcription Factor Regulates Cardiac Myocyte Size Downstream of AKT Signaling J. Biol. Chem., May 27, 2005; 280(21): 20814 - 20823. [Abstract] [Full Text] [PDF]
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T. Aoyama, T. Matsui, M. Novikov, J. Park, B. Hemmings, and A. Rosenzweig Serum and Glucocorticoid-Responsive Kinase-1 Regulates Cardiomyocyte Survival and Hypertrophic Response Circulation, April 5, 2005; 111(13): 1652 - 1659. [Abstract] [Full Text] [PDF]
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S. Guo, M. Lopez-Ilasaca, and V. J. Dzau Identification of Calcium-modulating Cyclophilin Ligand (CAML) as Transducer of Angiotensin II-mediated Nuclear Factor of Activated T Cells (NFAT) Activation J. Biol. Chem., April 1, 2005; 280(13): 12536 - 12541. [Abstract] [Full Text] [PDF]
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H.-P. Vosberg The ubiquitin-proteasome system may be involved in the pathogenesis of hypertrophic cardiomyopathy Cardiovasc Res, April 1, 2005; 66(1): 1 - 3. [Full Text] [PDF]
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Y. Liu, W. R. Randall, and M. F. Schneider Activity-dependent and -independent nuclear fluxes of HDAC4 mediated by different kinases in adult skeletal muscle J. Cell Biol., March 14, 2005; 168(6): 887 - 897. [Abstract] [Full Text] [PDF]
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B. Sanna, O. F. Bueno, Y.-S. Dai, B. J. Wilkins, and J. D. Molkentin Direct and Indirect Interactions between Calcineurin-NFAT and MEK1-Extracellular Signal-Regulated Kinase 1/2 Signaling Pathways Regulate Cardiac Gene Expression and Cellular Growth Mol. Cell. Biol., February 1, 2005; 25(3): 865 - 878. [Abstract] [Full Text] [PDF]
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J. Heineke, H. Ruetten, C. Willenbockel, S. C. Gross, M. Naguib, A. Schaefer, T. Kempf, D. Hilfiker-Kleiner, P. Caroni, T. Kraft, et al. Attenuation of cardiac remodeling after myocardial infarction by muscle LIM protein-calcineurin signaling at the sarcomeric Z-disc PNAS, February 1, 2005; 102(5): 1655 - 1660. [Abstract] [Full Text] [PDF]
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B. Schoffstall, A. Kataoka, A. Clark, and P. B. Chase Effects of Rapamycin on Cardiac and Skeletal Muscle Contraction and Crossbridge Cycling J. Pharmacol. Exp. Ther., January 1, 2005; 312(1): 12 - 18. [Abstract] [Full Text] [PDF]
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R. Arya, V. Kedar, J. R. Hwang, H. McDonough, H.-H. Li, J. Taylor, and C. Patterson Muscle ring finger protein-1 inhibits PKC{epsilon} activation and prevents cardiomyocyte hypertrophy J. Cell Biol., December 20, 2004; 167(6): 1147 - 1159. [Abstract] [Full Text] [PDF]
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B. C. Harrison, C. R. Roberts, D. B. Hood, M. Sweeney, J. M. Gould, E. W. Bush, and T. A. McKinsey The CRM1 Nuclear Export Receptor Controls Pathological Cardiac Gene Expression Mol. Cell. Biol., December 15, 2004; 24(24): 10636 - 10649. [Abstract] [Full Text] [PDF]
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A. M. Gillis, K. M. Kavanagh, H. J. Mathison, J. R. Somers, S. Zhan, and H. J. Duff Heart block in mice overexpressing calcineurin but not NF-AT3 Cardiovasc Res, December 1, 2004; 64(3): 488 - 495. [Abstract] [Full Text] [PDF]
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S. Mathew, E. Mascareno, and M. A. Q. Siddiqui A Ternary Complex of Transcription Factors, Nished and NFATc4, and Co-activator p300 Bound to an Intronic Sequence, Intronic Regulatory Element, Is Pivotal for the Up-regulation of Myosin Light Chain-2v Gene in Cardiac Hypertrophy J. Biol. Chem., September 24, 2004; 279(39): 41018 - 41027. [Abstract] [Full Text] [PDF]
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P. J. Schaeffer, A. R. Wende, C. J. Magee, J. R. Neilson, T. C. Leone, F. Chen, and D. P. Kelly Calcineurin and Calcium/Calmodulin-dependent Protein Kinase Activate Distinct Metabolic Gene Regulatory Programs in Cardiac Muscle J. Biol. Chem., September 17, 2004; 279(38): 39593 - 39603. [Abstract] [Full Text] [PDF]
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G. Selvetella, E. Hirsch, A. Notte, G. Tarone, and G. Lembo Adaptive and maladaptive hypertrophic pathways: points of convergence and divergence Cardiovasc Res, August 15, 2004; 63(3): 373 - 380. [Abstract] [Full Text] [PDF]
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B. Fiedler and K. C Wollert Interference of antihypertrophic molecules and signaling pathways with the Ca2+-calcineurin-NFAT cascade in cardiac myocytes Cardiovasc Res, August 15, 2004; 63(3): 450 - 457. [Abstract] [Full Text] [PDF]
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J. D Molkentin Calcineurin-NFAT signaling regulates the cardiac hypertrophic response in coordination with the MAPKs Cardiovasc Res, August 15, 2004; 63(3): 467 - 475. [Abstract] [Full Text] [PDF]
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V. P.M van Empel and L. J De Windt Myocyte hypertrophy and apoptosis: a balancing act Cardiovasc Res, August 15, 2004; 63(3): 487 - 499. [Abstract] [Full Text] [PDF]
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