This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 114/4/298    most recent CIRCULATIONAHA.105.608968v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by van Oort, R. J. Articles by De Windt, L. J. Search for Related Content PubMed PubMed Citation Articles by van Oort, R. J. Articles by De Windt, L. J. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Substance via MeSH Medline Plus Health Information Cardiomyopathy Heart Failure Related Collections Other heart failure Cell signalling/signal transduction Gene regulation Heart failure - basic studies 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:

				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]

				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]

				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]

				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]