Published online before print September 4, 2006, doi: 10.1161/CIRCULATIONAHA.106.637124
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2006;114:1159-1168.)
© 2006 American Heart Association, Inc.
Heart Failure |
Foxo Transcription Factors Blunt Cardiac Hypertrophy by Inhibiting Calcineurin Signaling
From the Donald W. Reynolds Cardiovascular Clinical Research Center (J.A.H.) and the Departments of Internal Medicine (Cardiology) (Y.G.N., K.B., N.W., M.O., N.S., A.D., J.C., G.L., D.J.M., R.D.G., B.A.R., J.A.H.), Pathology (D.C.), and Molecular Biology (R.D.G., J.A.H.), University of Texas Southwestern Medical Center, Dallas.
Correspondence to Dr Joseph A. Hill, Division of Cardiology, University of Texas Southwestern Medical Center, Dallas, TX 75390-8573. E-mail joseph.hill{at}UTSouthwestern.edu
Received December 6, 2005; de novo received April 29, 2006; revision received July 11, 2006; accepted July 14, 2006.
Background— Cellular hypertrophy requires coordinated regulation of progrowth and antigrowth mechanisms. In cultured neonatal cardiomyocytes, Foxo transcription factors trigger an atrophy-related gene program that counters hypertrophic growth. However, downstream molecular events are not yet well defined.
Methods and Results— Here, we report that expression of either Foxo1 or Foxo3 in cardiomyocytes attenuates calcineurin phosphatase activity and inhibits agonist-induced hypertrophic growth. Consistent with these results, Foxo proteins decrease calcineurin phosphatase activity and repress both basal and hypertrophic agonist-induced expression of MCIP1.4, a direct downstream target of the calcineurin/NFAT pathway. Furthermore, hearts from Foxo3-null mice exhibit increased MCIP1.4 abundance and a hypertrophic phenotype with normal systolic function at baseline. Together, these results suggest that Foxo proteins repress cardiac growth at least in part through inhibition of the calcineurin/NFAT pathway. Given that hypertrophic growth of the heart occurs in multiple contexts, our findings also suggest that certain hypertrophic signals are capable of overriding the antigrowth program induced by Foxo. Consistent with this, multiple hypertrophic agonists triggered inactivation of Foxo proteins in cardiomyocytes through a mechanism requiring the PI3K/Akt pathway. In addition, both Foxo1 and Foxo3 are phosphorylated and consequently inactivated in hearts undergoing hypertrophic growth induced by hemodynamic stress.
Conclusions— This study suggests that inhibition of the calcineurin/NFAT signaling cascade by Foxo and release of this repressive action by the PI3K/Akt pathway are important mechanisms whereby Foxo factors govern cell growth in the heart.
CLINICAL PERSPECTIVE
This article has been cited by other articles:
 |
|
 |
|
  Y. Li, W.-J. Wang, H. Cao, J. Lu, C. Wu, F.-Y. Hu, J. Guo, L. Zhao, F. Yang, Y.-X. Zhang, et al. Genetic association of FOXO1A and FOXO3A with longevity trait in Han Chinese populations Hum. Mol. Genet., December 15, 2009; 18(24): 4897 - 4904. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-C. Liu, C.-H. Chen, J.-J. Chen, and T.-H. Cheng Urotensin II Induces Rat Cardiomyocyte Hypertrophy via the Transient Oxidization of Src Homology 2-Containing Tyrosine Phosphatase and Transactivation of Epidermal Growth Factor Receptor Mol. Pharmacol., December 1, 2009; 76(6): 1186 - 1195. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Sengupta, J. D. Molkentin, and K. E. Yutzey FoxO Transcription Factors Promote Autophagy in Cardiomyocytes J. Biol. Chem., October 9, 2009; 284(41): 28319 - 28331. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Guo, Z. Gertsberg, N. Ozgen, and S. F. Steinberg p66Shc Links {alpha}1-Adrenergic Receptors to a Reactive Oxygen Species-Dependent AKT-FOXO3A Phosphorylation Pathway in Cardiomyocytes Circ. Res., March 13, 2009; 104(5): 660 - 669. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Hsu, T. Nagayama, N. Koitabashi, M. Zhang, L. Zhou, D. Bedja, K. L. Gabrielson, J. D. Molkentin, D. A. Kass, and E. Takimoto Phosphodiesterase 5 inhibition blocks pressure overload-induced cardiac hypertrophy independent of the calcineurin pathway Cardiovasc Res, February 1, 2009; 81(2): 301 - 309. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Donaldson, S. Eder, C. Baker, M. J. Aronovitz, A. D. Weiss, M. Hall-Porter, F. Wang, A. Ackerman, R. H. Karas, J. D. Molkentin, et al. Estrogen Attenuates Left Ventricular and Cardiomyocyte Hypertrophy by an Estrogen Receptor-Dependent Pathway That Increases Calcineurin Degradation Circ. Res., January 30, 2009; 104(2): 265 - 275. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Caporali and C. Emanueli Cardiovascular Actions of Neurotrophins Physiol Rev, January 1, 2009; 89(1): 279 - 308. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Chung and L. A. Leinwand Rescuing Cardiac Malfunction: The Roles of the Chaperone-Like Small Heat Shock Proteins Circ. Res., December 5, 2008; 103(12): 1351 - 1353. [Full Text] [PDF]
|
|
|
|
|
|
B. A. Rothermel and J. A. Hill Autophagy in Load-Induced Heart Disease Circ. Res., December 5, 2008; 103(12): 1363 - 1369. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. R.K. Kumarapeli, H. Su, W. Huang, M. Tang, H. Zheng, K. M. Horak, M. Li, and X. Wang {alpha}B-Crystallin Suppresses Pressure Overload Cardiac Hypertrophy Circ. Res., December 5, 2008; 103(12): 1473 - 1482. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W.-Q. Tan, K. Wang, D.-Y. Lv, and P.-F. Li Foxo3a Inhibits Cardiomyocyte Hypertrophy through Transactivating Catalase J. Biol. Chem., October 31, 2008; 283(44): 29730 - 29739. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
J. Huang, J. M. Shelton, J. A. Richardson, K. E. Kamm, and J. T. Stull Myosin Regulatory Light Chain Phosphorylation Attenuates Cardiac Hypertrophy J. Biol. Chem., July 11, 2008; 283(28): 19748 - 19756. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Canalis Notch Signaling in Osteoblasts Sci. Signal., April 29, 2008; 1(17): pe17 - pe17. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. J. Evans-Anderson, C. M. Alfieri, and K. E. Yutzey Regulation of Cardiomyocyte Proliferation and Myocardial Growth During Development by FOXO Transcription Factors Circ. Res., March 28, 2008; 102(6): 686 - 694. [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]
|
|
|
|
|
|
M. Kruger, C. Sachse, W. H. Zimmermann, T. Eschenhagen, S. Klede, and W. A. Linke Thyroid Hormone Regulates Developmental Titin Isoform Transitions via the Phosphatidylinositol-3-Kinase/ AKT Pathway Circ. Res., February 29, 2008; 102(4): 439 - 447. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. N. Papanicolaou, Y. Izumiya, and K. Walsh Forkhead Transcription Factors and Cardiovascular Biology Circ. Res., January 4, 2008; 102(1): 16 - 31. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. G. Ni, N. Wang, D. J. Cao, N. Sachan, D. J. Morris, R. D. Gerard, M. Kuro-o, B. A. Rothermel, and J. A. Hill FoxO transcription factors activate Akt and attenuate insulin signaling in heart by inhibiting protein phosphatases PNAS, December 18, 2007; 104(51): 20517 - 20522. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Lara-Pezzi, N. Winn, A. Paul, K. McCullagh, E. Slominsky, M. P. Santini, F. Mourkioti, P. Sarathchandra, S. Fukushima, K. Suzuki, et al. A naturally occurring calcineurin variant inhibits FoxO activity and enhances skeletal muscle regeneration J. Cell Biol., December 17, 2007; 179(6): 1205 - 1218. [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]
|
|
|
|
|
|
C. Patterson, C. Ike, P. W. Willis IV, G. A. Stouffer, and M. S. Willis The Bitter End: The Ubiquitin-Proteasome System and Cardiac Dysfunction Circulation, March 20, 2007; 115(11): 1456 - 1463. [Abstract] [Full Text] [PDF]
|
|