Donate Help Contact The AHA Sign In Home
American Heart Association
Circulation
Search: search_blue_button Advanced Search
Circulation. 2006;114:298-308
Published online before print July 17, 2006, doi: 10.1161/CIRCULATIONAHA.105.608968
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Data Supplement
Right arrow All Versions of this Article:
114/4/298    most recent
CIRCULATIONAHA.105.608968v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by van Oort, R. J.
Right arrow Articles by De Windt, L. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by van Oort, R. J.
Right arrow Articles by De Windt, L. J.
Related Collections
Right arrow Other heart failure
Right arrow Cell signalling/signal transduction
Right arrow Gene regulation
Right arrow Heart failure - basic studies
Right arrow Imaging

(Circulation. 2006;114:298-308.)
© 2006 American Heart Association, Inc.


Heart Failure

MEF2 Activates a Genetic Program Promoting Chamber Dilation and Contractile Dysfunction in Calcineurin-Induced Heart Failure

Ralph J. van Oort, MSc*; Eva van Rooij, PhD*; Meriem Bourajjaj, MSc; Joost Schimmel, BSc; Maurits A. Jansen, PhD; Roel van der Nagel, BSc; Pieter A. Doevendans, MD, PhD; Michael D. Schneider, MD, PhD; Cees J.A. van Echteld, PhD; Leon J. De Windt, PhD

From the Hubrecht Laboratory and Interuniversity Cardiology Institute Netherlands, Royal Netherlands Academy of Sciences, Utrecht, the Netherlands (R.J.v.O., E.v.R., M.B., J.S., R.v.d.N., L.J.D.W.); University Medical Center, Heart Lung Center Utrecht, Utrecht, the Netherlands (M.A.J., P.A.D., C.J.A.v.E.); and Center for Cardiovascular Development, Baylor College of Medicine, Houston, Tex (M.D.S.).

Correspondence to Leon J. De Windt, Hubrecht Laboratory, Uppsalalaan 8, 3584 CT Utrecht, Netherlands. E-mail dewindt{at}niob.knaw.nl

Received December 17, 2005; revision received May 13, 2006; accepted May 22, 2006.

Background— Hypertrophic growth, a risk factor for mortality in heart disease, is driven by reprogramming of cardiac gene expression. Although the transcription factor myocyte enhancer factor-2 (MEF2) is a common end point for several hypertrophic pathways, its precise cardiac gene targets and function in cardiac remodeling remain to be elucidated.

Methods and Results— We report the existence of synergistic interactions between the nuclear factor of activated T cells and MEF2 transcription factors triggered by calcineurin signaling. To circumvent the embryonic lethality and mitochondrial deficiency associated with germ-line null mutations for MEF2C and MEF2A respectively, we used conditional transgenesis to express a dominant-negative form of MEF2 in the murine postnatal heart and combined this with magnetic resonance imaging to assess MEF2 transcriptional function in Ca2+/calcineurin-induced cardiac remodeling. Surprisingly, end-diastolic and end-systolic ventricular dimensions and contractility were normalized in the presence of severely hypertrophied left ventricular walls on MEF2 inhibition in calcineurin transgenic mice. In line, we generated lines of transgenic mice expressing MEF2A in the heart, which displayed primarily chamber dilation. Microarray profiling indicated that MEF2 promotes a gene profile functioning primarily to or at the nucleus, cytoskeletal and microtubular networks, and mitochondria.

Conclusions— These findings assign a novel function to MEF2 transcription factors in the postnatal heart, where they activate a genetic program that minimally affects cardiac growth yet promotes chamber dilation, mechanical dysfunction, and dilated cardiomyopathy.


 

CLINICAL PERSPECTIVE




This article has been cited by other articles:


Home page
Circ. Res.Home page
E. Schroder, M. Byse, and J. Satin
L-Type Calcium Channel C Terminus Autoregulates Transcription
Circ. Res., June 19, 2009; 104(12): 1373 - 1381.
[Abstract] [Full Text] [PDF]


Home page
Mol. Cell. Biol.Home page
R. L. S. Perry, C. Yang, N. Soora, J. Salma, M. Marback, L. Naghibi, H. Ilyas, J. Chan, J. W. Gordon, and J. C. McDermott
Direct Interaction between Myocyte Enhancer Factor 2 (MEF2) and Protein Phosphatase 1{alpha} Represses MEF2-Dependent Gene Expression
Mol. Cell. Biol., June 15, 2009; 29(12): 3355 - 3366.
[Abstract] [Full Text] [PDF]


Home page
J. Biol. Chem.Home page
H. Feng, T. Cheng, J. H. Steer, D. A. Joyce, N. J. Pavlos, C. Leong, J. Kular, J. Liu, X. Feng, M. H. Zheng, et al.
Myocyte Enhancer Factor 2 and Microphthalmia-associated Transcription Factor Cooperate with NFATc1 to Transactivate the V-ATPase d2 Promoter during RANKL-induced Osteoclastogenesis
J. Biol. Chem., May 22, 2009; 284(21): 14667 - 14676.
[Abstract] [Full Text] [PDF]


Home page
Mol. Cell. Biol.Home page
S. Ikeda, A. He, S. W. Kong, J. Lu, R. Bejar, N. Bodyak, K.-H. Lee, Q. Ma, P. M. Kang, T. R. Golub, et al.
MicroRNA-1 Negatively Regulates Expression of the Hypertrophy-Associated Calmodulin and Mef2a Genes
Mol. Cell. Biol., April 15, 2009; 29(8): 2193 - 2204.
[Abstract] [Full Text] [PDF]


Home page
Cardiovasc ResHome page
P. Lacolley, P. Challande, M. Osborne-Pellegrin, and V. Regnault
Genetics and pathophysiology of arterial stiffness
Cardiovasc Res, March 1, 2009; 81(4): 637 - 648.
[Abstract] [Full Text] [PDF]


Home page
Acta Biochim Biophys SinHome page
S. Sun, Y. Gui, Y. Wang, L. Qian, X. Liu, Q. Jiang, and H. Song
Effects of methotrexate on the developments of heart and vessel in zebrafish
Acta Biochim Biophys Sin, January 1, 2009; 41(1): 86 - 96.
[Abstract] [Full Text] [PDF]


Home page
CirculationHome page
P. A. da Costa Martins, M. Bourajjaj, M. Gladka, M. Kortland, R. J. van Oort, Y. M. Pinto, J. D. Molkentin, and L. J. De Windt
Conditional Dicer Gene Deletion in the Postnatal Myocardium Provokes Spontaneous Cardiac Remodeling
Circulation, October 7, 2008; 118(15): 1567 - 1576.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
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]


Home page
DevelopmentHome page
Y. Hinits and S. M. Hughes
Mef2s are required for thick filament formation in nascent muscle fibres
Development, July 1, 2007; 134(13): 2511 - 2519.
[Abstract] [Full Text] [PDF]


Home page
Proc. Natl. Acad. Sci. USAHome page
S. Fisch, S. Gray, S. Heymans, S. M. Haldar, B. Wang, O. Pfister, L. Cui, A. Kumar, Z. Lin, S. Sen-Banerjee, et al.
Kruppel-like factor 15 is a regulator of cardiomyocyte hypertrophy
PNAS, April 24, 2007; 104(17): 7074 - 7079.
[Abstract] [Full Text] [PDF]