Atrophic Remodeling of the Cardiomyocyte

描述（由申请人提供）：心脏肥大和萎缩均激活胎儿基因程序，而心脏质量的变化方向相反。这种二分法留下了一个关键的差距，以确定这些途径，传达方向性，因为左心室肥厚的回归降低了心血管疾病的发病率和死亡率的风险。我们已经表明，大鼠心脏的机械卸载激活泛素蛋白酶体途径，并减少心脏质量。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，并降低了心肌细胞的大小。总体假设是，在动物模型和衰竭的人类心脏中，在存在促肥大信号的情况下，未负载心脏中蛋白质降解途径的激活诱导逆向重构。第一个具体目标将定义体内决定心肌细胞大小减小的信号传导途径。第二个具体目标是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，我们将定义FOXO 3a/ Mafbx/Atrogin-1/ MuRF-1通路在肥大啮齿动物心脏中基因表达、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中心肌细胞萎缩的信号通路。在这里，我们将研究信号通路调节萎缩之前和之后，在失败的人类心脏机械卸载与左心室辅助装置。由于胰岛素是肌细胞萎缩的有效负调节剂（例如，胰岛素降低Mafbx/Atrogin-1表达），我们将在存在和不存在葡萄糖-胰岛素-钾的情况下，在冠状动脉旁路手术期间偶然获得的左心室心肌的系列样品中检查萎缩的介质。我们的长期目标是确定转录和转录后机制，调节肥大的存在下，促肥大信号的回归，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.