The heart responds to stress signals by hypertrophic growth, which is the first step towards heart failure (HF). The genetic pattern underlying HF remains largely elusive. Although the transcription factor Myocyte Enhancer Factor-2 (MEF2) is known to be a common endpoint for several hypertrophic signaling pathways, its precise role in myocardial remodeling is unknown. To this end, we pursued comprehensive gain- and loss-of-function approaches for MEF2 transcriptional activity in heart muscle in vitro and in vivo. We generated transgenic mice overexpressing MEF2 in the heart, which resulted in HF. In line, adenoviral delivery of MEF2 to cultured cardiomyocytes induced myocyte elongation, myofibril degeneration, and redistribution of focal adhesions, as seen in failing hearts. We also generated mice expressing a dominant negative form of MEF2 and crossed these mice with calcineurin transgenic mice, a model for cardiac hypertrophy and heart failure. This did not prevent cardiac hypertrophy, but protected the mice from HF. To identify MEF2 target genes, we generated inducible stable cardiac cell lines, expressing the active form of MEF2, and performed microarray analysis. Functional clustering of MEF2 target genes revealed an overrepresentation of genes involved in cytoskeletal remodeling and cell-matrix adhesion. We describe myotonic dystrophy protein kinase (DMPK) as a direct transcriptional target for MEF2. By siRNA-mediated knockdown of DMPK expression, we demonstrate the involvement of this gene in the pathological aspects of MEF2 induced cardiomyocyte remodeling. Given the resemblance between MEF2 induced cardiac remodeling and the cardiac phenotype of mice lacking Muscle LIM Protein (MLP), an established mouse model for inherited dilated cardiomyopathy, we analyzed MEF2 transcription factor activity in MLP knockout mice by genetic crossbreeding with MEF2 reporter mice. Following confirmation that MEF2 activity was severely upregulated, we used conditional transgenesis to express a dominant-negative form of MEF2 (DNMEF2) in the murine MLP deficient heart and combined this with echocardiographic analysis to examine the effect on cardiac remodeling. Surprisingly, histological and functional analyses indicated that MEF2 inhibition in MLP knockout mice did not effect the genesis of dilated cardiomyopathy. Finally, the significance of MEF2 transcriptional activity was assessed in the setting of a more physiological model of biomechanical stress in the form of chronic murine pressure overload using conditional transgenesis to express a dominant-negative form of MEF2 (DNMEF2) in the postnatal heart. Surprisingly, echocardiography indicated that MEF2 inhibition did not improve end-diastolic and end-systolic ventricular dimensions and contractility as observed in calcineurin transgenic hearts with conditional MEF2 inhibition. In fact, cardiac function was significantly worsened in the setting of MEF2 inhibition, which could be correlated with specific defects in mitochondrial adaptation during pressure overload. Taken together, in this thesis we demonstrate that MEF2 activation in the heart does not evoke the classic hypertrophic response, yet promotes a gene program primarily involved in processes associated with dilated cardiomyopathy. Although MEF2 activation is required for maladaptive cardiac remodeling downstream of calcineurin signaling, its activity is not the sole trigger in certain forms of dilated cardiomyopathy, and is even necessary for the adaptive response of the heart during pressure overload
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