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（由申请人提供）：本次更新提案的目标涉及 多学科综合方法来理解的机制 心脏肥大的开始。我们实验室和其他实验室的研究表明 表明除了血压控制之外还有其他因素导致 高血压引起心脏肥大。我们假设心脏 肥大是由机械或体液信号引发的 心肌，并且心肌反过来产生触发因素 蛋白质合成。我们已经从自发性中鉴定出肌营养因子 高血压大鼠心脏（SHR）。这种 12.5-kD 因子可刺激肌细胞 生长，已被纯化至同质、测序和克隆。我们已经展示了 肌营养蛋白增加原癌基因的转录水平，刺激 两者中 B 肌球蛋白重链的转录水平和肌营养蛋白的 ANF 水平 SHR 和人心。我们所有的发现都提供了丰富的令人信服的证据 有证据表明肌营养蛋白在刺激肌细胞生长中发挥重要作用。 我们最近的成就是开发了转基因小鼠模型 心脏中肌营养蛋白过度表达。肌营养蛋白的特异性过度表达， 通过 mRNA 和蛋白质的测量，在心肌中导致 心肌病进展为心力衰竭。心脏肥大是 与多灶性纤维化、肌细胞坏死和显着相关 射血分数降低。该转基因小鼠模型的开发 不仅为研究肥大的起始过程开辟了新的大门 还可以跟踪在特定时间点发生的分子变化 肥大转变为心力衰竭。更重要的是，我们的数据显示 肌营养蛋白过度表达导致肌肥大的发展 进展为心力衰竭。现在，我们关注的是肌营养蛋白如何发挥其作用 对心肌细胞生长的影响以及在此过程中发生的分子变化 肥厚的开始到进展为心力衰竭。我们提出一个 分子、遗传、细胞和病理生理学方法的结合。 我们的具体目标是（1）研究发生在 过度表达肌营养蛋白的转基因小鼠模型，分析发生的变化 作为肌营养蛋白的结果，特别是在肥大进展到 心脏衰竭; (2) 阐明信号通路激活的步骤 肌营养蛋白过度表达导致心力衰竭； (3) 干预 在药理学上预防/逆转不同点的心脏肥大； (4) 通过超声心动图确定与心脏功能相关的心脏功能 上述实验中观察到的分子变化。预期结果来自 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看到的非常相似 在人类心肌病中。所提出的实验将改善我们的 了解肌营养蛋白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开发 控制或预防肥厚和心力衰竭的发展 人心。