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.

心室肥厚是一种适应性过程，其中 心脏的体积和质量是由多种生理因素引起的 以及病理性刺激。后者中最常见的是压力过载。 全身性高血压引起的肥厚(POH)。起始室 与这一过程相关的重塑允许左心室 通过对墙进行正火处理，良好地适应增加的外部工作量 压力。如果异常负荷持续存在，心腔的改变 和肌肉特性在充血性心力衰竭(CHF)中最终通过 分子机制知之甚少。总体假设 对于这个研究方案来说，是补偿之间的过渡 压力超负荷肥厚和充血性心力衰竭的结果-来自 心肌肥厚诱因的独特组合改变， 成年心肌细胞固有的转导和靶蛋白。这个 该项目的主要目标是开发一种小动物模型 压力超负荷性肥厚与充血性心力衰竭的关系 以特定的分子和生物化学事件为基础 过渡。为了验证这一假设并实现这一目标，我们 将考察五个具体目标：1)开发一种小动物模型，该模型 显示代偿的POH(正常的心肌细胞功能，正常的腔室 功能，无全身或肺充血)和CHF(异常心肌细胞 功能、心腔功能受抑和肺充血) 胸主动脉降支环扎术。2)检视潜力 蛋白质合成中对机械变形的差异响应 在这两个阶段中从脑室提取成年心肌细胞； 3)研究蛋白质差异激活的潜在作用 通过代偿性POH和CHF之间的机械应力作用；4) 检测P-肌球蛋白对拉伸敏感的转录调控 具有可变长度β-MHC启动子序列的体内重链 横主动脉致POH后与CAT报告基因杂交 5)研究钙循环中的潜在差异。 蛋白质(SR-ATPase、磷蛋白、兰尼定受体、钙调素) 可能发生在POH和CHF之间的稳定状态的mRNA，蛋白质和 并将这些差异与改变的机制联系起来 和细胞内钙动力学的变化。 孤立的兰登多夫灌流心脏。