TRANSITION BETWEEN PRESSURE OVERLOAD HYPERTROPHY AND HEART FAILURE

压力过载、肥大和心力衰竭之间的转变

• 批准号: 6242348
• 负责人: Richard A. Walsh
• 金额: $ 24.4万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-01-01 至 1997-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6242348
• 关键词: calcium binding protein; chloramphenicol acetyltransferase; congestive heart failure; disease /disorder model; genetic promoter element; genetic transcription; genetically modified animals; guinea pigs; heart cell; high energy compound; high performance liquid chromatography; intracardiac pressure; isolation perfusion; laboratory mouse; mechanical stress; messenger RNA; myosins; northern blottings; protein biosynthesis; protein kinase C; reporter genes; stretch reflex; ventricular hypertrophy; western blottings

Ventricular hypertrophy is an adaptive process wherein an increase in cardiac volume and mass occurs in response to a variety of physiologic and pathologic stimuli. Most common among the latter is pressure overload hypertrophy (POH) consequent to systemic hypertension. Initial chamber remodeling associated with this process permits the left ventricle to favorably adapt to the increased external work by normalizing wall stress. If the abnormal workload persists, alterations in cardiac chamber and muscle properties eventuate in congestive heart failure (CHF) by molecular mechanisms which are poorly understood. The overall hypothesis for this research program is that the transition between compensated pressure overload hypertrophy and congestive heart failure results-from distinctive combinatorial alterations in cardiac hypertrophy triggers, transducers and target proteins intrinsic to the adult cardiomyocyte. The major objective of this project is to develop a small animal model of pressure overload hypertrophy and congestive heart failure to elucidate stage specific molecular and biochemical events which underlie this transition. To test this hypothesis and to achieve this objective, we will examine five Specific Aims: 1) To develop a small animal model which manifests compensated POH (normal myocyte function, normal chamber function, no systemic or pulmonary congestion) and CHF (abnormal myocyte function, depressed chamber function and pulmonary congestion) by descending thoracic aortic banding. 2) To examine the potential differential response in protein synthesis to mechanical deformation of adult cardiomyocytes extracted from ventricles during these two stages; 3) To study the potential role of differential activation of protein kinase C by mechanical stress between compensated POH and CHF; 4) To examine the stretch sensitive transcriptional regulation of P-myosin heavy chain in vivo with variable length beta-MHC promoter sequences hybridized to a CAT reporter gene after POH produced by transverse aortic banding; and 5) To study potential differences in the calcium cycling proteins (SR ATPase, phospholamban, ryanodine receptor, calsequestrin) which may occur between POH and CHF at the steady state mRNA, protein and functional levels and to relate these differences to altered mechanics and intracellular calcium kinetics of the isolated cardiomyocyte and the isolated Langendorff perfused heart.

心室肥大是一个适应性过程，其中心室肥厚的增加 心脏的体积和质量是对各种生理反应的反应而发生的 和病理刺激。后者中最常见的是压力过载 全身性高血压导致的肥大（POH）。初始室 与此过程相关的重塑允许左心室 通过使墙壁正常化，有利地适应增加的外部工作 压力。如果异常的工作负荷持续存在，心室就会发生变化 和肌肉特性最终导致充血性心力衰竭（CHF） 人们对分子机制知之甚少。总体假设 对于这个研究计划来说，补偿之间的过渡 压力超负荷导致肥厚和充血性心力衰竭 心脏肥大触发因素的独特组合改变， 成人心肌细胞固有的传感器和靶蛋白。这 该项目的主要目标是开发一种小动物模型 压力超负荷肥厚和充血性心力衰竭的阐明 阶段特定的分子和生化事件是其基础 过渡。 为了检验这个假设并实现这个目标，我们 将研究五个具体目标：1）开发一种小动物模型 表现出代偿性 POH（正常肌细胞功能、正常心室 功能，无全身或肺充血）和 CHF（异常肌细胞 功能、心室功能低下和肺充血） 胸降主动脉带。 2）考察潜力 蛋白质合成对机械变形的不同反应 在这两个阶段从心室提取成体心肌细胞； 3）研究蛋白质差异激活的潜在作用 补偿性 POH 和 CHF 之间的机械应力导致激酶 C； 4) 至 检查 P-肌球蛋白的拉伸敏感性转录调控 具有可变长度β-MHC启动子序列的体内重链 与横主动脉产生的 POH 后的 CAT 报告基因杂交 条带； 5) 研究钙循环的潜在差异 蛋白质（SR ATP酶、受磷蛋白、ryanodine受体、calsequestrin） 这可能发生在 POH 和 CHF 之间的稳定状态 mRNA、蛋白质和 功能水平并将这些差异与改变的机制联系起来 和分离的心肌细胞的细胞内钙动力学和 孤立的 Langendorff 灌注心脏。