Xu Jian, Gong Nanling L, Bodi Ilona, Aronow Bruce J, Backx Peter H, Molkentin Jeffery D
Departments of Pharmacology and Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio 45229, USA.
J Biol Chem. 2006 Apr 7;281(14):9152-62. doi: 10.1074/jbc.M510217200. Epub 2006 Feb 9.
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.
心肌肥大和扩张是由神经内分泌因子和/或促有丝分裂原介导的，也通过内部的拉伸和应力敏感信号通路介导，这些信号通路进而通过特定的信号通路转导心脏基因表达的改变。被称为肌细胞增强因子2（MEF2）的转录因子家族被认为是心脏转录程序的信号响应介质。例如，已知利用钙调神经磷酸酶、钙调蛋白依赖性蛋白激酶和丝裂原活化蛋白激酶的肥大信号通路均可影响MEF2活性。在此，我们证明MEF2转录因子可诱导扩张型心肌病和心肌细胞延长。具体而言，多个心脏特异性过表达MEF2A或MEF2C的转基因小鼠品系在基线时即出现心肌病，或在压力超负荷刺激后更易发生暴发性疾病。与MEF2A和MEF2C相关的心肌病反应不会因活化的钙调神经磷酸酶而进一步改变，这表明MEF2在该反应中独立于钙调神经磷酸酶发挥作用。在培养的心肌细胞中，MEF2A、MEF2C和MEF2-VP16的过表达诱导肌节紊乱和局部延长。从机制上讲，MEF2A和MEF2C各自在心脏中编程了相似的基因表达改变谱，包括细胞外基质重塑、离子处理和代谢基因。事实上，用MEF2A对培养的心肌细胞进行腺病毒转染，或对来自MEF2A转基因成年小鼠心脏的心肌细胞进行转染，均显示瞬时外向钾离子电流降低，这与在转基因小鼠中观察到的基因表达改变一致，并部分提示了MEF2依赖性心肌病的近端机制。
