TRANSITION BETWEEN PRESSURE OVERLOAD HYPERTROPHY AND HEART FAILURE

心室肥大是一种适应性过程， 心脏体积和质量的发生是对各种生理变化的反应， 和病理刺激。后者中最常见的是压力过载 肥大（POH）是全身性高血压的结果。初始反应室 与此过程相关的重塑允许左心室 有利地适应通过正火壁增加的外部工作 应力如果不正常的工作负荷持续， 充血性心力衰竭（CHF）的肌肉特性， 分子机制还知之甚少。总体假设 在这个研究项目中， 压力超负荷肥大和充血性心力衰竭的结果， 心脏肥大触发器的独特组合改变， 转换器和靶蛋白的内在的成年心肌细胞。的 该项目的主要目标是开发一种小动物模型， 压力超负荷肥大和充血性心力衰竭，以阐明 阶段特异性分子和生物化学事件， 过渡 为了验证这一假设并实现这一目标，我们 将研究五个具体目标：1）建立一个小动物模型， 表现出代偿性POH（正常肌细胞功能，正常心腔 功能，无全身或肺充血）和CHF（异常肌细胞 功能、降低的心腔功能和肺充血）， 胸降主动脉缩窄术 2)为了检验 蛋白质合成对机械变形的不同反应 在这两个阶段从心室中提取的成年心肌细胞; 3)研究蛋白质的差异激活在细胞凋亡中的潜在作用 激酶C通过补偿POH和CHF之间的机械应力; 4） 检测P-肌球蛋白的牵张敏感性转录调节 具有可变长度β-MHC启动子序列的体内重链 与CAT报告基因杂交后，由横主动脉产生POH 5）研究钙循环中的电位差异 蛋白质（SR ATP酶、受磷蛋白、ryanodine受体、钙螯合蛋白） 这可能发生在POH和CHF之间的稳态mRNA，蛋白质和 功能水平，并将这些差异与改变力学 和细胞内钙动力学的分离的心肌细胞和 离体Langendorff灌流心脏。

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.