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Updated: Aug 11, 2026
Isolation, Culture, and Functional Characterization of Adult Mouse Cardiomyoctyes
Published on: September 24, 2013
Myocyte enhancer factors 2A and 2C induce dilated cardiomyopathy in transgenic mice
Jian Xu1, Nanling L Gong, Ilona Bodi
1Departments of Pharmacology and Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio 45229, USA.
Abstract:
Cardiac hypertrophy and dilation are mediated by neuroendocrine factors and/or mitogens as well as through internal stretch- and stress-sensitive signaling pathways, which in turn transduce alterations in cardiac gene expression through specific signaling pathways. The transcription factor family known as myocyte enhancer factor 2 (MEF2) has been implicated as a signal-responsive mediator of the cardiac transcriptional program. For example, known hypertrophic signaling pathways that utilize calcineurin, calmodulin-dependent protein kinase, and MAPKs can each affect MEF2 activity. Here we demonstrate that MEF2 transcription factors induced dilated cardiomyopathy and lengthening of myocytes. Specifically, multiple transgenic mouse lines with cardiac-specific overexpression of MEF2A or MEF2C presented with cardiomyopathy at base line or were predisposed to more fulminant disease following pressure overload stimulation. The cardiomyopathic response associated with MEF2A and MEF2C was not further altered by activated calcineurin, suggesting that MEF2 functions independently of calcineurin in this response. In cultured cardiomyocytes, MEF2A, MEF2C, and MEF2-VP16 overexpression induced sarcomeric disorganization and focal elongation. Mechanistically, MEF2A and MEF2C each programmed similar profiles of altered gene expression in the heart that included extracellular matrix remodeling, ion handling, and metabolic genes. Indeed, adenoviral transfection of cultured cardiomyocytes with MEF2A or of myocytes from the hearts of MEF2A transgenic adult mice showed reduced transient outward K(+) currents, consistent with the alterations in gene expression observed in transgenic mice and partially suggesting a proximal mechanism underlying MEF2-dependent cardiomyopathy.
Insights
Myocyte enhancer factor 2 (MEF2) transcription factors directly cause dilated cardiomyopathy and myocyte lengthening. Overexpression of MEF2A or MEF2C in mice led to heart disease, independent of calcineurin signaling.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Gene Regulation
Background:
- Cardiac hypertrophy and dilation involve neuroendocrine factors, mitogens, and mechanical stress signaling.
- Myocyte enhancer factor 2 (MEF2) transcription factors are key mediators in cardiac transcriptional programs.
- MEF2 activity is modulated by hypertrophic signaling pathways like calcineurin, CaMK, and MAPKs.
Purpose of the Study:
- To investigate the role of MEF2 transcription factors in inducing cardiac hypertrophy and dilation.
- To determine if MEF2 functions independently of the calcineurin signaling pathway in cardiomyopathy.
- To elucidate the molecular mechanisms underlying MEF2-mediated cardiac dysfunction.
Main Methods:
- Generation of transgenic mouse lines with cardiac-specific overexpression of MEF2A or MEF2C.
- Assessment of cardiomyopathy in transgenic mice at baseline and under pressure overload conditions.
- In vitro studies using cultured cardiomyocytes to examine MEF2 effects on cellular structure and gene expression.
- Adenoviral transfection of cardiomyocytes to study MEF2-induced changes in ion currents.
Main Results:
- Cardiac-specific overexpression of MEF2A or MEF2C induced dilated cardiomyopathy and myocyte lengthening in mice.
- The cardiomyopathic phenotype was observed independently of activated calcineurin signaling.
- Overexpression of MEF2A, MEF2C, or MEF2-VP16 in cultured cardiomyocytes caused sarcomeric disorganization and elongation.
- MEF2A and MEF2C altered gene expression profiles related to extracellular matrix remodeling, ion handling, and metabolism.
- Reduced transient outward K+ currents were observed in MEF2-overexpressing cardiomyocytes, suggesting a proximal mechanism.
Conclusions:
- MEF2 transcription factors are potent inducers of dilated cardiomyopathy and myocyte elongation.
- MEF2-mediated cardiomyopathy operates independently of the calcineurin signaling pathway.
- MEF2A and MEF2C orchestrate significant changes in cardiac gene expression, impacting key cellular functions and contributing to disease pathogenesis.
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