Atrophic Remodeling of the Cardiomyocyte

描述(申请人提供)：心脏肥大和萎缩都会激活胎儿基因程序，而心脏质量的变化方向相反。这种二分法在识别传递方向性的通路方面留下了一个关键的空白，因为左心室肥厚的消退降低了心血管发病率和死亡率的风险。我们已经证明，机械卸载大鼠心脏激活了泛素蛋白酶体途径，并减少了心脏质量。在分离的心肌细胞中，我们发现叉头转录因子FOXOSa的激活增加了两种泛素连接酶(Mafbx/Atrogin-1和Murf-1)的表达，并缩小了心肌细胞的大小。总体假设是，无论是在动物模型中还是在衰竭的人类心脏中，蛋白质降解途径的激活都会在促肥大信号存在的情况下诱导反向重塑。第一个具体目标将确定决定体内心肌细胞大小减少的信号通路。第二个特定目标将通过激活蛋白质降解的信号通路来确定体外和体内心肌细胞肥大的可逆性。在功能获得和功能丧失策略中，我们将确定FOXO3a/Mafbx/Atrogin-1/Murf-1通路在肥大啮齿动物心脏基因表达、萎缩和功能调节中的作用。第三个具体目标将定义调节人类心脏心肌细胞萎缩的信号通路。在这里，我们将研究在使用左心室辅助装置机械卸载之前和之后，衰竭的人心脏中调节萎缩的信号通路。由于胰岛素是心肌细胞萎缩的强有力的负调节因子(例如，胰岛素降低Mafbx/Atrogin-1的表达)，我们将在有无葡萄糖-胰岛素-钾存在和不存在的情况下，在冠状动脉旁路手术期间偶然获得的一系列左室心肌样本中检测萎缩的介体。我们的长期目标是确定在促肥厚信号存在的情况下调节肥厚消退的转录和转录后机制，并将来自动物的研究结果转化为可行的临床策略。

DESCRIPTION (provided by applicant): Both hypertrophy and atrophy of the heart activate the fetal gene program, while cardiac mass changes in opposite directions. This dichotomy leaves a critical gap to identify those pathways that convey directionality, because regression of left ventricular hypertrophy decreases the risk for cardiovascular morbidity and mortality. We have shown that mechanical unloading of the rat heart activates the ubiquitin proteasome pathway and decreases cardiac mass. In isolated myocytes we found that activation of the forkhead transcription factor FOXOSa increases the expression of two ubiquitin ligases (Mafbx/Atrogin-1 and MuRF-1) and decreases cardiomyocyte size. The overall hypothesis is that the activation of pathways of protein degradation in the unloaded heart induces reverse remodeling in the presence of pro-hypertrophic signals, both in animal models and in the failing human heart. The first specific aim will define the signaling pathways determining a decrease in cardiomyocyte size in vivo. The second specific aim will determine the reversibility of cardiomyocyte hypertrophy in vitro and in vivo by activating signaling pathways of protein degradation. In gain-of-function and in loss-of-function strategies we will define the role of the FOXO3a/ Mafbx/Atrogin-1/ MuRF-1 pathway in the regulation of gene expression, atrophy, and function in the hypertrophied rodent heart. The third specific aim will define signaling pathways regulating cardiomyocyte atrophy in the human heart. Here, we will examine signaling pathways regulating atrophy in the failing human heart before and after mechanical unloading with a left ventricular assist device. Because insulin is a potent negative regulator of myocyte atrophy (e.g. insulin decreases Mafbx/Atrogin-1 expression), we will examine mediators of atrophy in serial samples of left ventricular myocardium incidentally obtained during coronary artery bypass surgery in the presence and absence of glucose-insulin-potassium. Our long-term objective is to define transcriptional and post-transcriptional mechanisms that regulate regression of hypertrophy in the presence of pro-hypertrophic signaling and to translate findings derived from animals to workable clinical strategies.