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: 6110354
• 负责人: Richard A. Walsh
• 金额: $ 26.28万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-01 至 1999-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6110354
• 关键词: calcium binding protein; cardiac myocytes; chloramphenicol acetyltransferase; congestive heart failure; disease /disorder model; genetic promoter element; genetic transcription; genetically modified animals; guinea pigs; 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.

心室肥大是一种自适应过程，其中增加 心脏体积和质量是针对多种生理学的响应 和病理刺激。后者最常见的是压力超负荷 肥大（POH）造成全身性高血压。初始室 与此过程相关的重塑允许左心室 通过标准化墙来适应增加的外部工作 压力。如果工作量异常持续，则心脏室的改变 和肌肉特性在充血性心力衰竭（CHF）中发生 分子机制知之甚少。总体假设 对于该研究计划，补偿之间的过渡 压力超负荷肥大和充血性心力衰竭结果 心脏肥大触发器的独特组合改变， 换能器和靶向成人心肌细胞固有的蛋白质。这 该项目的主要目的是开发一个小动物模型 压力超负荷肥大和充血性心力衰竭以阐明 阶段特定的分子和生化事件，这是基于此的 过渡。 为了检验这一假设并实现这一目标，我们 将研究五个具体目标：1）开发一个小动物模型，该模型 表现为补偿POH（正常的心肌功能，正常腔室 功能，无系统性或肺部充血）和CHF（异常心肌细胞 功能，腔室功能和肺部充血） 下降的胸主动脉谱带。 2）检查潜力 蛋白质合成对机械变形的差异反应 在这两个阶段，从心室提取的成年心肌细胞； 3）研究蛋白质差异激活的潜在作用 激酶C通过补偿POH和CHF之间的机械应力； 4）到 检查P杂菌素的拉伸敏感转录调控 重链在体内，长度可变β-MHC启动子序列 横向主动脉产生POH后，与猫报告基因杂交 乐队5）研究钙循环的潜在差异 蛋白质（SR ATPase，Phospholamban，ryanodine受体，Calsequesterin） 在稳态mRNA，蛋白质和 功能水平并将这些差异与改变的力学联系 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。