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

Abstract

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 Ca 2ϩ /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.

Kruppel-like factor 15 is a regulator of cardiomyocyte hypertrophy

“…Members of the MEF2 family are well known to critically regulate heart development and recent studies strongly support a role for this pathway in the adult heart's response to stress. For example, transgenic overexpression of MEF2A or MEF2C leads to a dosedependent dilated cardiomyopathy that is dramatically worsened following pressure overload (16,17). Consistent with this role, overexpression of a dominant-negative MEF2 normalized ventricular dimensions and contractility in calcineurin transgenic mice (16).…”

“…Prohypertrophic stimuli activate a series of intracellular signal transduction pathways that result in the induction of MEF2 and GATA4 DNA-binding activity and nuclear accumulation of NFATs. In vitro studies have demonstrated that overexpression of either MEF2 factors or GATA4 induces cardiomyocyte hypertrophy (10,16). Cardiac-specific transgenic overexpression of either MEF2 (16,17) or constitutively active calcineurin-A (18) cause cardiomyopathies characterized by increased cardiac mass, chamber dilation, and left-ventricular systolic dysfunction.…”

“…In vitro studies have demonstrated that overexpression of either MEF2 factors or GATA4 induces cardiomyocyte hypertrophy (10,16). Cardiac-specific transgenic overexpression of either MEF2 (16,17) or constitutively active calcineurin-A (18) cause cardiomyopathies characterized by increased cardiac mass, chamber dilation, and left-ventricular systolic dysfunction. High levels of GATA4 overexpression in the heart also result in a severe cardiomyopathy and premature death, and modest overexpression results in cardiac hypertrophy (10).…”

“…High levels of GATA4 overexpression in the heart also result in a severe cardiomyopathy and premature death, and modest overexpression results in cardiac hypertrophy (10). Multiple lines of evidence indicate that these transcriptional pathways cooperate in the development of cardiac dysfunction (16). Despite the increasing body of knowledge describing the biology of transcriptional activators of cardiac hypertrophy, there is much less information regarding transcriptional repressors of hypertrophy (6).…”

Selective translation of mRNAs in the left ventricular myocardium of the mouse in response to acute pressure overload

“…MEF2D is a member of myocyte enhancer factor-2 family of transcription factors that are activated by Ca 2+ /Calmodulin-dependent signaling pathways, and regulate expression of structural genes in the cardiocyte [20]. Although changes in MEF2 levels are relatively modest during cardiac hypertrophy, recent findings have linked MEF2 to expression of target genes associated with myocardial remodeling, for example cytoskeletal components and ion channels [21,22]. FGF-2 and VEGF are members of the heparin binding protein family of growth factors.…”