Initiation of Cardiac Hypertrophy in Hypertension

描述(申请人提供)：本续期建议书的目标包括 用多学科综合的方法来理解心力衰竭的发病机制 启动心肌肥厚。我们实验室和其他实验室的研究已经 证明了血压控制以外的因素是导致 高血压患者启动心肌肥厚。我们假设心脏 肥大是由机械的或体液的信号启动的 心肌进而产生一种触发因子 蛋白质合成。我们已经从自发的肌营养素中鉴定出了这种因子 高血压大鼠心脏(SHR)。这种12.5-kD的因子，刺激心肌细胞 生长，已被提纯到均一，测序和克隆。我们已经展示了 肌营养因子增加原癌基因的转录水平，刺激 B-肌球蛋白重链的转录水平和肌营养素的心钠素水平 自发性高血压和人类心脏。我们所有的发现都提供了大量令人信服的证据 有证据表明肌营养因子在刺激心肌细胞生长方面起着重要作用。 我们最新的成就是开发了转基因小鼠模型 在心脏中过度表达肌营养因子。肌营养因子的特异性过表达， 根据信使核糖核酸和蛋白质的测定，心肌中的 发展为心力衰竭的心肌病。心肌肥厚 与多发性局灶性纤维化、心肌细胞坏死相关，并显著 射血分数降低。转基因小鼠模型的建立 不仅为研究肥厚的起始过程打开了新的大门 也是为了跟踪在特定时间点发生的分子变化 从肥厚到心力衰竭的转变。更重要的是，我们的数据显示 肌营养因子的过度表达导致了肥大的发展 进展为心力衰竭。现在，我们关注的是肌营养因子是如何发挥其作用的 对心肌细胞生长的影响和发生的分子变化 开始肥厚发展为心力衰竭。我们提出了一个 结合了分子、遗传、细胞和病理生理学方法。 我们的具体目标是：(1)研究生物大分子的变化 过表达肌营养因子的转基因小鼠模型，分析发生的变化 作为肌营养素的结果，特别是在肥厚进展到 心力衰竭；(2)阐明信号通路中激活的步骤 肌营养素过度表达导致心力衰竭；(3)干预 从药理上预防/逆转不同穴位的心肌肥厚；(4) 通过超声心动图来确定与心脏功能相关的 上述实验中观察到的分子变化。预期的结果来自 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所见非常相似 在人类心肌病中。拟议的实验将改善我们的 肌营养素的作用机制及其病理生理研究进展 意义。我们的研究可能会导致开发治疗工具 控制或预防心脏肥厚和心力衰竭的发展 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.