MEF2 activates a genetic program promoting chamber dilation and contractile dysfunction in calcineurin-induced heart failure.
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.


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.
van Oort
Ralph J
RJ
Hubrecht Laboratory, and Interuniversity Cardiology Institute Netherlands, Royal Netherlands Academy of Sciences, Utrecht, Netherlands.
van Rooij
Eva
E
Bourajjaj
Meriem
M
Schimmel
Joost
J
Jansen
Maurits A
MA
van der Nagel
Roel
R
Doevendans
Pieter A
PA
Schneider
Michael D
MD
van Echteld
Cees J A
CJ
De Windt
Leon J
LJ
D000818:Animals; D019703:Calcineurin / Q000494:pharmacology*; D006332:Cardiomegaly / Q000235:genetics; D002311:Cardiomyopathy, Dilated / Q000209:etiology* / Q000235:genetics; D020869:Gene Expression Profiling; D006333:Heart Failure / Q000139:chemically induced / Q000503:physiopathology*; D064326:MEF2 Transcription Factors; D008279:Magnetic Resonance Imaging; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction; D018006:Myogenic Regulatory Factors / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction
D064326:MEF2 Transcription Factors; C578036:Mef2a protein, mouse; D018006:Myogenic Regulatory Factors; D019703:Calcineurin