Initiation of Cardiac Hypertrophy in Hypertension

高血压引起心脏肥大

• 批准号: 6638323
• 负责人: Subha Sen
• 金额: $ 37万
• 依托单位: CLEVELAND CLINIC FOUNDATION
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-12-01 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6638323
• 关键词: biological signal transduction; cardiac myocytes; cell growth regulation; disease /disorder etiology; echocardiography; gene expression; genetically modified animals; growth factor; heart failure; heart function; hypertension; hypertrophic myocardiopathy; laboratory mouse; mechanical stress; mitogen activated protein kinase; myocardium; pathologic process; protein biosynthesis; protein kinase C

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.

描述（申请人提供）：该续签提案的目标涉及 一种理解机制的多学科综合方法 心脏肥大的启动。我们实验室和其他人的研究 证明血压控制以外的其他因素是负责的 在高血压中引发心脏肥大。我们假设心脏 肥大是由机械或体液的信号引发的 心肌和心肌反过来产生触发因素 蛋白质合成。我们自发地从 高血压大鼠心（SHR）。这12.5 kD因子刺激心肌细胞 生长已被纯化为同质性，测序和克隆。我们已经显示了 肌营养蛋白增加了原始基因的转录水平，刺激了 B肌球蛋白重链和ANF水平的成绩单水平在两者中 SHR和人类的心。我们所有的发现提供了很多令人信服的 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转基因小鼠模型 过表达心脏的肌营养蛋白。肌营养素的特定过表达， 通过mRNA和蛋白质测量，在心肌中导致 心脏衰竭的心肌病。心脏肥大是 与多重局灶性纤维化，心肌坏死和显着 减少射血分数。该转基因小鼠模型的开发 已经打开了新的门，不仅研究了肥大的启动过程 但也遵循在特定点发生的分子变化 肥大过渡到心力衰竭。更重要的是，我们的数据显示 肌营养蛋白的过表达导致肥大的发展 发展为心力衰竭。现在，我们专注于肌营养蛋白如何施加 对肌细胞生长的影响以及在此期间发生的分子变化 肥大的开始，发展为心力衰竭。我们提出了一个 分子，遗传，细胞和病理生理方法的结合。 我们的具体目的是（1）研究在 过表达肌蛋白的转基因小鼠模型，分析发生的变化 由于肌营养素的结果，尤其是在肥大进展为 心脏衰竭; （2）阐明由信号通路中激活的信号通路中的步骤 肌营养性过表达，导致心力衰竭； （3）干预 在药理学上，以预防/回归各个点的心脏肥大； （4） 通过超声心动图来定义心脏功能与 在上述实验中观察到的分子变化。预期的结果 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所见的变化非常相似 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理及其病理生理 意义。我们的研究可能导致开发治疗工具 控制或防止肥大和心力衰竭的发展 人心。