Initiation of Cardiac Hypertrophy in Hypertension

描述（由申请人提供）：本更新提案的目标包括 一个多学科的综合方法来理解的机制， 开始心脏肥大。我们实验室和其他机构的研究表明， 表明血压控制以外的因素是导致 引发高血压的心脏肥大。我们假设心脏 肥大是由机械或体液信号启动的， 心肌，心肌反过来又产生一种因子， 蛋白质合成我们已经鉴定出肌营养因子， 高血压大鼠心脏（SHR）。这种12.5 kD的因子，刺激心肌细胞 生长，已纯化至同质，测序和克隆。我们已经表明 肌营养因子增加原癌基因的转录水平， B-肌球蛋白重链的转录水平和肌营养素的ANF水平， SHR和人类心脏。我们所有的发现都提供了大量令人信服的证据 肌营养素在刺激肌细胞生长中起重要作用的证据。 我们最近的成就是开发了一种转基因小鼠模型 过度表达肌营养素肌营养素的特异性过表达， 如通过mRNA和蛋白质测量的，在心肌中导致 发展为心力衰竭的心肌病心肌肥厚是 与多发性局灶性纤维化、肌细胞坏死和显著 射血分数降低。这种转基因小鼠模型的开发 不仅为研究肥大的起始过程， 还可以跟踪在细胞分裂过程中特定点发生的分子变化， 肥大向心力衰竭的转变。更重要的是，我们的数据显示 肌营养因子过度表达导致肥大的发展， 进展到心力衰竭现在，我们关注肌营养素如何发挥其 对肌细胞生长的影响以及在此过程中发生的分子变化 从肥大开始到发展为心力衰竭。我们提出了一个 分子、遗传、细胞和病理生理学方法的组合。 我们的具体目标是：（1）研究发生在细胞中的分子变化， 转基因小鼠模型过表达肌营养素，分析发生的变化， 作为肌营养因子的结果，特别是在肥大进展到 心力衰竭;（2）阐明信号通路中的步骤， 肌营养因子过度表达导致心力衰竭;（3）干预 预防/逆转各点的心脏肥大;（4） 通过超声心动图确定与心脏功能相关的心脏功能， 在上述实验中观察到的分子变化。的预期结果 这项研究与人类高血压问题直接相关， 肥大，因为观察到的分子变化与观察到的非常相似 在人类心肌病中。拟议的实验将改善我们的 了解肌营养素的作用机制及其病理生理学 意义我们的研究可能会导致治疗工具的发展， 控制或预防肥大和心力衰竭的发展， 人类的心脏

DESCRIPTION (provided by applicant): The goal of this renewal proposal involves a multidisciplinary integrative approach to understand the mechanism o initiation of cardiac hypertrophy. Studies from our laboratory and others have demonstrated that factors other than blood pressure control are responsible for initiating cardiac hypertrophy in hypertension. We hypothesize that cardiac hypertrophy is initiated by a signal, either mechanical or humoral, to the myocardium and that the myocardium in turn produces a factor that triggers protein synthesis. We have identified the factor myotrophin from spontaneously hypertensive rat hearts (SHR). This 12.5-kD factor, which stimulates myocyte growth, has been purified to homogeneity, sequenced, and cloned. We have shown that myotrophin increases transcript levels of proto-oncogenes, stimulates transcript levels of B-myosin heavy chain and ANF levels of myotrophin in both SHR and human hearts. All our findings have provided a wealth of convincing evidence that myotrophin plays an important role in stimulating myocyte growth. Our most recent achievement was the development of a transgenic mouse model overexpressing myotrophin in the heart. Specific overexpression of myotrophin, as measured by both mRNA and proteins, in the myocardium resulted in cardiomyopathy that advanced to heart failure. Cardiac hypertrophy was associated with multiple focal fibrosis, myocyte necrosis and significant reduction of ejection fraction. The development of this transgenic mouse model has opened up new doors to study not only the initiation process of hypertrophy but also to follow molecular changes that occur at specific points during the transition of hypertrophy to heart failure. More importantly, our data showed that myotrophin overexpression resulted in the development of hypertrophy that advances to heart failure. Now, we are focusing on how myotrophin exerts its effect on myocyte growth and the molecular changes that take place during initiation of hypertrophy to its advancement to heart failure. We propose a combination of molecular, genetic, cellular and pathophysiological approaches. Our specific aims are (1) to study molecular changes that occur in the transgenic mouse model overexpressing myotrophin, analyzing changes that occur as a consequence of myotrophin, especially during progression of hypertrophy to heart failure; (2) to elucidate steps in the signaling pathway activated by myotrophin overexpression that lead to heart failure; (3) to intervene pharmacologically to prevent/regress cardiac hypertrophy at various points; (4) to define, by echocardiography, the cardiac functions correlated with the molecular changes observed in the above experiments. The results expected from this study are directly related to problems of human hypertension and hypertrophy, as the molecular changes observed are very similar to those seen in human cardiomyopathy. The proposed experiments will improve our understanding of myotrophin's mechanism of action and its pathophysiological significance. Our studies may lead to the development of therapeutic tools for controlling or preventing the development of hypertrophy and heart failure in human hearts.