Circulation Research. 2003
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
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on May 7, 2003
Revised on November 14, 2003
Accepted on November 14, 2003
Calcineurin/NFAT Coupling Participates in Pathological, but not Physiological, Cardiac Hypertrophy
Benjamin J. Wilkins ;
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.
* To whom correspondence should be addressed. 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 A
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
This article has been cited by other articles:
 |
|
 |
|
  A. Y. M. Chan, V. W. Dolinsky, C.-L. M. Soltys, B. Viollet, S. Baksh, P. E. Light, and J. R. B. Dyck Resveratrol Inhibits Cardiac Hypertrophy via AMP-activated Protein Kinase and Akt J. Biol. Chem., August 29, 2008; 283(35): 24194 - 24201. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Bourajjaj, A.-S. Armand, P. A. da Costa Martins, B. Weijts, R. van der Nagel, S. Heeneman, X. H. Wehrens, and L. J. De Windt NFATc2 Is a Necessary Mediator of Calcineurin-dependent Cardiac Hypertrophy and Heart Failure J. Biol. Chem., August 8, 2008; 283(32): 22295 - 22303. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Sama, D. M. Mathis, J. L. Furman, H. M. Abdul, I. A. Artiushin, S. D. Kraner, and C. M. Norris Interleukin-1{beta}-dependent Signaling between Astrocytes and Neurons Depends Critically on Astrocytic Calcineurin/NFAT Activity J. Biol. Chem., August 8, 2008; 283(32): 21953 - 21964. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. R. Houser and J. D. Molkentin Does Contractile Ca2+ Control Calcineurin-NFAT Signaling and Pathological Hypertrophy in Cardiac Myocytes? Sci. Signal., June 24, 2008; 1(25): pe31 - pe31. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. M. Heidrich, K. Zhang, M. Estrada, Y. Huang, F. J. Giordano, and B. E. Ehrlich Chromogranin B Regulates Calcium Signaling, Nuclear Factor {kappa}B Activity, and Brain Natriuretic Peptide Production in Cardiomyocytes Circ. Res., May 23, 2008; 102(10): 1230 - 1238. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Karatas, B. Hegner, L. J. de Windt, F. C. Luft, C. Schubert, V. Gross, Y. J. Akashi, D. Gurgen, U. Kintscher, A. C. da Costa Goncalves, et al. Deoxycorticosterone Acetate-Salt Mice Exhibit Blood Pressure-Independent Sexual Dimorphism Hypertension, April 1, 2008; 51(4): 1177 - 1183. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. Hill and E. N. Olson Cardiac Plasticity N. Engl. J. Med., March 27, 2008; 358(13): 1370 - 1380. [Full Text] [PDF]
|
|
|
|
 |
|
 I. Pinz, S. E. Ostroy, K. Hoyer, H. Osinska, J. Robbins, J. D. Molkentin, and J. S. Ingwall Calcineurin-induced energy wasting in a transgenic mouse model of heart failure Am J Physiol Heart Circ Physiol, March 1, 2008; 294(3): H1459 - H1466. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. A. Woodcock, X.-J. Du, M. E. Reichelt, and R. M. Graham Cardiac {alpha}1-adrenergic drive in pathological remodelling Cardiovasc Res, February 1, 2008; 77(3): 452 - 462. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. R. Rana, C. Zobel, E. Saygili, K. Brixius, F. Gramley, T. Schimpf, K. Mischke, D. Frechen, C. Knackstedt, R. H. G. Schwinger, et al. A simple device to apply equibiaxial strain to cells cultured on flexible membranes Am J Physiol Heart Circ Physiol, January 1, 2008; 294(1): H532 - H540. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. T. Gurda, L. Guo, S.-H. Lee, J. D. Molkentin, and J. A. Williams Cholecystokinin Activates Pancreatic Calcineurin-NFAT Signaling In Vitro and In Vivo Mol. Biol. Cell, January 1, 2008; 19(1): 198 - 206. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Sena, I. R. Rasmussen, A. R. Wende, A. P. McQueen, H. A. Theobald, N. Wilde, R. O. Pereira, S. E. Litwin, J. P. Berger, and E. D. Abel Cardiac Hypertrophy Caused by Peroxisome Proliferator- Activated Receptor-{gamma} Agonist Treatment Occurs Independently of Changes in Myocardial Insulin Signaling Endocrinology, December 1, 2007; 148(12): 6047 - 6053. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. D. Folmes, L. A. Witters, M. F. Allard, M. E. Young, and J. R. B. Dyck The AMPK {gamma}1 R70Q mutant regulates multiple metabolic and growth pathways in neonatal cardiac myocytes Am J Physiol Heart Circ Physiol, December 1, 2007; 293(6): H3456 - H3464. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Frank, C. Kuhn, M. van Eickels, D. Gehring, C. Hanselmann, S. Lippl, R. Will, H. A. Katus, and N. Frey Calsarcin-1 Protects Against Angiotensin-II Induced Cardiac Hypertrophy Circulation, November 27, 2007; 116(22): 2587 - 2596. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. H. Purcell, B. J. Wilkins, A. York, M. K. Saba-El-Leil, S. Meloche, J. Robbins, and J. D. Molkentin Genetic inhibition of cardiac ERK1/2 promotes stress-induced apoptosis and heart failure but has no effect on hypertrophy in vivo PNAS, August 28, 2007; 104(35): 14074 - 14079. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Mu, L. D. Brown, Y. Liu, and M. F. Schneider Roles of the calcineurin and CaMK signaling pathways in fast-to-slow fiber type transformation of cultured adult mouse skeletal muscle fibers Physiol Genomics, August 20, 2007; 30(3): 300 - 312. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Nishida, N. Onohara, Y. Sato, R. Suda, M. Ogushi, S. Tanabe, R. Inoue, Y. Mori, and H. Kurose G{alpha}12/13-mediated Up-regulation of TRPC6 Negatively Regulates Endothelin-1-induced Cardiac Myofibroblast Formation and Collagen Synthesis through Nuclear Factor of Activated T Cells Activation J. Biol. Chem., August 10, 2007; 282(32): 23117 - 23128. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Oka, J. Xu, R. A. Kaiser, J. Melendez, M. Hambleton, M. A. Sargent, A. Lorts, E. W. Brunskill, G. W. Dorn II, S. J. Conway, et al. Genetic Manipulation of Periostin Expression Reveals a Role in Cardiac Hypertrophy and Ventricular Remodeling Circ. Res., August 3, 2007; 101(3): 313 - 321. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. E. Hannigan, J. G. Coles, and S. Dedhar Integrin-Linked Kinase at the Heart of Cardiac Contractility, Repair, and Disease Circ. Res., May 25, 2007; 100(10): 1408 - 1414. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. E. Merten, Y. Jiang, and Y. J. Kang Zinc Inhibits Doxorubicin-Activated Calcineurin Signal Transduction Pathway in H9c2 Embryonic Rat Cardiac Cells Experimental Biology and Medicine, May 1, 2007; 232(5): 682 - 689. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. R. Bergman, J. R. Teerlink, R. Mahimkar, L. Li, B.-Q. Zhu, A. Nguyen, S. Dahi, J. S. Karliner, and D. H. Lovett Cardiac matrix metalloproteinase-2 expression independently induces marked ventricular remodeling and systolic dysfunction Am J Physiol Heart Circ Physiol, April 1, 2007; 292(4): H1847 - H1860. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. A. Parsons, D. P. Millay, M. A. Sargent, F. J. Naya, E. M. McNally, H. L. Sweeney, and J. D. Molkentin Genetic Disruption of Calcineurin Improves Skeletal Muscle Pathology and Cardiac Disease in a Mouse Model of Limb-Girdle Muscular Dystrophy J. Biol. Chem., March 30, 2007; 282(13): 10068 - 10078. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. M. Nilsson, Z.-W. Sun, J. Nilsson, I. Nordstrom, Y.-W. Chen, J. D. Molkentin, D. Wide-Swensson, P. Hellstrand, M.-L. Lydrup, and M. F. Gomez Novel blocker of NFAT activation inhibits IL-6 production in human myometrial arteries and reduces vascular smooth muscle cell proliferation Am J Physiol Cell Physiol, March 1, 2007; 292(3): C1167 - C1178. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Nieves-Cintron, G. C. Amberg, C. B. Nichols, J. D. Molkentin, and L. F. Santana Activation of NFATc3 Down-regulates the beta1 Subunit of Large Conductance, Calcium-activated K+ Channels in Arterial Smooth Muscle and Contributes to Hypertension J. Biol. Chem., February 2, 2007; 282(5): 3231 - 3240. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Goruppi, R. D. Patten, T. Force, and J. M. Kyriakis Helix-Loop-Helix Protein p8, a Transcriptional Regulator Required for Cardiomyocyte Hypertrophy and Cardiac Fibroblast Matrix Metalloprotease Induction Mol. Cell. Biol., February 1, 2007; 27(3): 993 - 1006. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. R. McMullen, F. Amirahmadi, E. A. Woodcock, M. Schinke-Braun, R. D. Bouwman, K. A. Hewitt, J. P. Mollica, L. Zhang, Y. Zhang, T. Shioi, et al. Protective effects of exercise and phosphoinositide 3-kinase(p110{alpha}) signaling in dilated and hypertrophic cardiomyopathy PNAS, January 9, 2007; 104(2): 612 - 617. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. E. Merten, Y. Jiang, W. Feng, and Y. J. Kang Calcineurin Activation Is Not Necessary for Doxorubicin-Induced Hypertrophy in H9c2 Embryonic Rat Cardiac Cells: Involvement of the Phosphoinositide 3-Kinase-Akt Pathway J. Pharmacol. Exp. Ther., November 1, 2006; 319(2): 934 - 940. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Schiekofer, I. Shiojima, K. Sato, G. Galasso, Y. Oshima, and K. Walsh Microarray analysis of Akt1 activation in transgenic mouse hearts reveals transcript expression profiles associated with compensatory hypertrophy and failure Physiol Genomics, October 11, 2006; 27(2): 156 - 170. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Fornaro, P. M. Burch, W. Yang, L. Zhang, C. E. Hamilton, J. H. Kim, B. G. Neel, and A. M. Bennett SHP-2 activates signaling of the nuclear factor of activated T cells to promote skeletal muscle growth J. Cell Biol., October 9, 2006; 175(1): 87 - 97. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Koulmann, V. Novel-Chate, A. Peinnequin, R. Chapot, B. Serrurier, N. Simler, H. Richard, R. Ventura-Clapier, and X. Bigard Cyclosporin A Inhibits Hypoxia-induced Pulmonary Hypertension and Right Ventricle Hypertrophy Am. J. Respir. Crit. Care Med., September 15, 2006; 174(6): 699 - 705. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Heger and G. Euler iNOS - Another cardiac target of calcineurin Cardiovasc Res, September 1, 2006; 71(4): 612 - 614. [Full Text] [PDF]
|
|
|
|
 |
|
 H. Nakayama, B. J. Wilkin, I. Bodi, and J. D. Molkentin Calcineurin-dependent cardiomyopathy is activated by TRPC in the adult mouse heart FASEB J, August 1, 2006; 20(10): 1660 - 1670. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Chen, S. P. Shevtsov, E. Hsich, L. Cui, S. Haq, M. Aronovitz, R. Kerkela, J. D. Molkentin, R. Liao, R. N. Salomon, et al. The {beta}-Catenin/T-Cell Factor/Lymphocyte Enhancer Factor Signaling Pathway Is Required for Normal and Stress-Induced Cardiac Hypertrophy Mol. Cell. Biol., June 15, 2006; 26(12): 4462 - 4473. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. F. Rossow, K. W. Dilly, and L. F. Santana Differential Calcineurin/NFATc3 Activity Contributes to the Ito Transmural Gradient in the Mouse Heart Circ. Res., May 26, 2006; 98(10): 1306 - 1313. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Liu, B. J. Wilkins, Y. J. Lee, H. Ichijo, and J. D. Molkentin Direct Interaction and Reciprocal Regulation between ASK1 and Calcineurin-NFAT Control Cardiomyocyte Death and Growth Mol. Cell. Biol., May 15, 2006; 26(10): 3785 - 3797. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Sanna, E. B. Brandt, R. A. Kaiser, P. Pfluger, S. A. Witt, T. R. Kimball, E. van Rooij, L. J. De Windt, M. E. Rothenberg, M. H. Tschop, et al. Modulatory calcineurin-interacting proteins 1 and 2 function as calcineurin facilitators in vivo PNAS, May 9, 2006; 103(19): 7327 - 7332. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
K. Walsh Akt Signaling and Growth of the Heart Circulation, May 2, 2006; 113(17): 2032 - 2034. [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 J. Nilsson, L. M. Nilsson, Y.-W. Chen, J. D. Molkentin, D. Erlinge, and M. F. Gomez High Glucose Activates Nuclear Factor of Activated T Cells in Native Vascular Smooth Muscle Arterioscler. Thromb. Vasc. Biol., April 1, 2006; 26(4): 794 - 800. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
E. M. McNally Hypertrophic Cardiomyopathy: Exercise and Eat Right Circ. Res., March 3, 2006; 98(4): 443 - 445. [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|