© 2001 American Heart Association, Inc.
Integrative Physiology |
The Dual-Specificity Phosphatase MKP-1 Limits the Cardiac Hypertrophic Response In Vitro and In Vivo
From the Department of Pediatrics, University of Cincinnati, Children’s Hospital Medical Center, Division of Molecular Cardiovascular Biology, 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 jeff.molkentin{at}chmcc.org
Abstract—Mitogen-activated protein kinase (MAPK) signaling pathways are important regulators of cell growth, proliferation, and stress responsiveness. A family of dual-specificity MAP kinase phosphatases (MKPs) act as critical counteracting factors that directly regulate the magnitude and duration of p38, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK) activation. Here we show that constitutive expression of MKP-1 in cultured primary cardiomyocytes using adenovirus-mediated gene transfer blocked the activation of p38, JNK1/2, and ERK1/2 and prevented agonist-induced hypertrophy. Transgenic mice expressing physiological levels of MKP-1 in the heart showed (1) no activation of p38, JNK1/2, or ERK1/2; (2) diminished developmental myocardial growth; and (3) attenuated hypertrophy in response to aortic banding and catecholamine infusion. These results provide further evidence implicating MAPK signaling factors as obligate regulators of cardiac growth and hypertrophy and demonstrate the importance of dual-specificity phosphatases as counterbalancing regulatory factors in the heart.
Key Words: hypertrophy • cardiac function • mice, transgenic • mitogen-activated protein kinase • phosphatase
This article has been cited by other articles:
 |
|
 |
|
  J. Davis, M. V. Westfall, D. Townsend, M. Blankinship, T. J. Herron, G. Guerrero-Serna, W. Wang, E. Devaney, and J. M. Metzger Designing Heart Performance by Gene Transfer Physiol Rev, October 1, 2008; 88(4): 1567 - 1651. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Boutros, E. Chevet, and P. Metrakos Mitogen-Activated Protein (MAP) Kinase/MAP Kinase Phosphatase Regulation: Roles in Cell Growth, Death, and Cancer Pharmacol. Rev., September 1, 2008; 60(3): 261 - 310. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Bermudez, S. Lopez, Y. M. Pacheco, J. Villar, F. J.G. Muriana, J. D. Hoheisel, A. Bauer, and R. Abia Influence of postprandial triglyceride-rich lipoproteins on lipid-mediated gene expression in smooth muscle cells of the human coronary artery Cardiovasc Res, July 15, 2008; 79(2): 294 - 303. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X.-K. Tong and E. Hamel Transforming Growth Factor-beta1 Impairs Endothelin-1-Mediated Contraction of Brain Vessels by Inducing Mitogen-Activated Protein (MAP) Kinase Phosphatase-1 and Inhibiting p38 MAP Kinase Mol. Pharmacol., December 1, 2007; 72(6): 1476 - 1483. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Yamamoto, K. Kataoka, T. Yamashita, Y. Tokutomi, Y.-F. Dong, S. Matsuba, H. Ogawa, and S. Kim-Mitsuyama Role of Xanthine Oxidoreductase in the Reversal of Diastolic Heart Failure by Candesartan in the Salt-Sensitive Hypertensive Rat Hypertension, October 1, 2007; 50(4): 657 - 662. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Wang Mitogen-Activated Protein Kinases in Heart Development and Diseases Circulation, September 18, 2007; 116(12): 1413 - 1423. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Ito, T. Suganami, Y. Miyamoto, Y. Yoshimasa, M. Takeya, Y. Kamei, and Y. Ogawa Role of MAPK Phosphatase-1 in the Induction of Monocyte Chemoattractant Protein-1 during the Course of Adipocyte Hypertrophy J. Biol. Chem., August 31, 2007; 282(35): 25445 - 25452. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Lemmens, V. F.M. Segers, M. Demolder, M. Michiels, P. Van Cauwelaert, and G. W. De Keulenaer Endogenous inhibitors of hypertrophy in concentric versus eccentric hypertrophy Eur J Heart Fail, April 1, 2007; 9(4): 352 - 356. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Fujita, S. Ryser, S. Tortola, I. Piuz, and W. Schlegel Gene-specific recruitment of positive and negative elongation factors during stimulated transcription of the MKP-1 gene in neuroendocrine cells Nucleic Acids Res., February 16, 2007; 35(3): 1007 - 1017. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. R. Morissette, S. A. Cook, S. Foo, G. McKoy, N. Ashida, M. Novikov, M. Scherrer-Crosbie, L. Li, T. Matsui, G. Brooks, et al. Myostatin Regulates Cardiomyocyte Growth Through Modulation of Akt Signaling Circ. Res., July 7, 2006; 99(1): 15 - 24. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. A. Babiker, D. Lips, R. Meyer, E. Delvaux, P. Zandberg, B. Janssen, G. van Eys, C. Grohe, and P. A. Doevendans Estrogen Receptor {beta} Protects the Murine Heart Against Left Ventricular Hypertrophy Arterioscler. Thromb. Vasc. Biol., July 1, 2006; 26(7): 1524 - 1530. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Hilfiker-Kleiner, A. Hilfiker, M. Castellazzi, K. C. Wollert, C. Trautwein, H. Schunkert, and H. Drexler JunD attenuates phenylephrine-mediated cardiomyocyte hypertrophy by negatively regulating AP-1 transcriptional activity Cardiovasc Res, July 1, 2006; 71(1): 108 - 117. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. K. Olson, K. N. Protheroe, T. D. Scholz, and J. L. Segar The Mitogen-Activated Protein Kinases and Akt Are Developmentally Regulated in the Chronically Anemic Fetal Sheep Heart Reproductive Sciences, April 1, 2006; 13(3): 157 - 165. [Abstract] [PDF]
|
|
|
|
 |
|
 E. A. Tallant, C. M. Ferrario, and P. E. Gallagher Angiotensin-(1-7) inhibits growth of cardiac myocytes through activation of the mas receptor Am J Physiol Heart Circ Physiol, October 1, 2005; 289(4): H1560 - H1566. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. P. J. Buermans, E. M. Redout, A. E. Schiel, R. J. P. Musters, M. Zuidwijk, P. P. Eijk, C. van Hardeveld, S. Kasanmoentalib, F. C. Visser, B. Ylstra, et al. Microarray analysis reveals pivotal divergent mRNA expression profiles early in the development of either compensated ventricular hypertrophy or heart failure Physiol Genomics, May 11, 2005; 21(3): 314 - 323. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Palm-Leis, U. S. Singh, B. S. Herbelin, G. D. Olsovsky, K. M. Baker, and J. Pan Mitogen-activated Protein Kinases and Mitogen-activated Protein Kinase Phosphatases Mediate the Inhibitory Effects of All-trans Retinoic Acid on the Hypertrophic Growth of Cardiomyocytes J. Biol. Chem., December 24, 2004; 279(52): 54905 - 54917. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
S. E Hardt and J. Sadoshima Negative regulators of cardiac hypertrophy Cardiovasc Res, August 15, 2004; 63(3): 500 - 509. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Tongers, B. Fiedler, D. Konig, T. Kempf, G. Klein, J. Heineke, T. Kraft, S. Gambaryan, S. M Lohmann, H. Drexler, et al. Heme oxygenase-1 inhibition of MAP kinases, calcineurin/NFAT signaling, and hypertrophy in cardiac myocytes Cardiovasc Res, August 15, 2004; 63(3): 545 - 552. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Kaiser, O. F. Bueno, D. J. Lips, P. A. Doevendans, F. Jones, T. F. Kimball, and J. D. Molkentin Targeted Inhibition of p38 Mitogen-activated Protein Kinase Antagonizes Cardiac Injury and Cell Death Following Ischemia-Reperfusion in Vivo J. Biol. Chem., April 9, 2004; 279(15): 15524 - 15530. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. J. Lips, L. J. deWindt, D. J.W. van Kraaij, and P. A. Doevendans Molecular determinants of myocardial hypertrophy and failure: alternative pathways for beneficial and maladaptive hypertrophy Eur. Heart J., May 2, 2003; 24(10): 883 - 896. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N C Sundgren, G D Giraud, P J S Stork, J G Maylie, and K L Thornburg Angiotensin II stimulates hyperplasia but not hypertrophy in immature ovine cardiomyocytes J. Physiol., May 1, 2003; 548(3): 881 - 891. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Dash, A. G Schmidt, A. Pathak, M. J Gerst, D. Biniakiewicz, V. J Kadambi, B. D Hoit, W. T Abraham, and E. G Kranias Differential regulation of p38 mitogen-activated protein kinase mediates gender-dependent catecholamine-induced hypertrophy Cardiovasc Res, March 1, 2003; 57(3): 704 - 714. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Xu, I. A Arenas, S. J Armstrong, and S. T Davidge Estrogen modulation of left ventricular remodeling in the aged heart Cardiovasc Res, February 1, 2003; 57(2): 388 - 394. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Fiedler, S. M. Lohmann, A. Smolenski, S. Linnemuller, B. Pieske, F. Schroder, J. D. Molkentin, H. Drexler, and K. C. Wollert Inhibition of calcineurin-NFAT hypertrophy signaling by cGMP-dependent protein kinase type I in cardiac myocytes PNAS, August 20, 2002; 99(17): 11363 - 11368. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Kerkela, S. Pikkarainen, T. Majalahti-Palviainen, H. Tokola, and H. Ruskoaho Distinct Roles of Mitogen-activated Protein Kinase Pathways in GATA-4 Transcription Factor-mediated Regulation of B-type Natriuretic Peptide Gene J. Biol. Chem., April 12, 2002; 277(16): 13752 - 13760. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. C. Braz, O. F. Bueno, L. J. De Windt, and J. D. Molkentin PKC{alpha} regulates the hypertrophic growth of cardiomyocytes through extracellular signal-regulated kinase1/2 (ERK1/2) J. Cell Biol., March 4, 2002; 156(5): 905 - 919. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Liao, D. Georgakopoulos, A. Kovacs, M. Zheng, D. Lerner, H. Pu, J. Saffitz, K. Chien, R.-P. Xiao, D. A. Kass, et al. The in vivo role of p38 MAP kinases in cardiac remodeling and restrictive cardiomyopathy PNAS, September 26, 2001; (2001) 211086598. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. van Eickels, C. Grohe, J. P.M. Cleutjens, B. J. Janssen, H. J.J. Wellens, and P. A. Doevendans 17{beta}-Estradiol Attenuates the Development of Pressure-Overload Hypertrophy Circulation, September 18, 2001; 104(12): 1419 - 1423. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-T. TSENG, R. KOPEL, J. P. STABILA, B. G. MCGONNIGAL, T. T. NGUYEN, P. A. GRUPPUSO, and J. F. PADBURY {beta}-Adrenergic receptors ({beta}AR) regulate cardiomyocyte proliferation during early postnatal life FASEB J, September 1, 2001; 15(11): 1921 - 1926. [Abstract] [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]
|
|
|
|
|
|
D. C. H. Ng, C. S. Long, and M. A. Bogoyevitch A Role for the Extracellular Signal-regulated Kinase and p38 Mitogen-activated Protein Kinases in Interleukin-1beta -stimulated Delayed Signal Tranducer and Activator of Transcription 3 Activation, Atrial Natriuretic Factor Expression, and Cardiac Myocyte Morphology J. Biol. Chem., July 27, 2001; 276(31): 29490 - 29498. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Liao, D. Georgakopoulos, A. Kovacs, M. Zheng, D. Lerner, H. Pu, J. Saffitz, K. Chien, R.-P. Xiao, D. A. Kass, et al. The in vivo role of p38 MAP kinases in cardiac remodeling and restrictive cardiomyopathy PNAS, October 9, 2001; 98(21): 12283 - 12288. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. C. Braz, O. F. Bueno, L. J. De Windt, and J. D. Molkentin PKC{alpha} regulates the hypertrophic growth of cardiomyocytes through extracellular signal-regulated kinase1/2 (ERK1/2) J. Cell Biol., March 4, 2002; 156(5): 905 - 919. [Abstract] [Full Text] [PDF]
|
|