CONTRACTILE FORCE AND CALCIUM HANDLING IN HEART FAILURE

充血性心力衰竭(CHE)与心肌细胞受损有关 功能。其含量和异构体分布的变化 参与钙离子转运的收缩蛋白和关键蛋白有 在瑞士法郎被发现。充血性心力衰竭的力量发育减少可能是由于 钙处理改变，收缩蛋白功能降低，或从 这些因素的综合作用。它们之间的精确关系 心肌蛋白质合成的改变和心肌细胞功能受损 然而，瑞士法郎仍不确定。当前的总目标 研究建议是确定减少的细胞机制 实验性充血性心力衰竭动物模型的心肌功能。我们的数据 表示在终末期CHF时功能受抑 刺激和在有皮肤的心脏小梁中 心肌细胞。然而，最近的初步数据表明，抑郁 收缩的痉挛力量先于抑制的肌丝功能， 这表明发育早期钙处理的变化 心力衰竭导致心功能低下，而肌丝改变 功能与过渡到明显的心力衰竭有关。在……里面 因此，这项提议将具体检验以下假设： 1)心力衰竭发展过程中心肌力发展减少 是由收缩过程中细胞内钙浓度降低引起的： 将直接测量准确和校准的细胞内钙 钙离子荧光探针法在离体心小梁中的应用 使用最新开发的一种严格控制肌节长度的条件 技术；2)引起向失代偿期终末期心力衰竭的过渡 通过降低最大力量发育、钙反应和三磷酸腺苷 收缩装置的水解率：力量发展，钙 响应性和ATP水解率将以 作为游离钙功能的通透性小梁。激光衍射 将使用技术来准确测量和控制肌节 长度，以便获得准确和明确的数据。贯穿始终 充血性心力衰竭、钙调节蛋白和肌丝蛋白的研究进展 水平和基因表达将通过Western和 Northern印迹分别与原位功能和 血流动力学数据。预计这些实验将提供 新的和明确的数据。关于蜂窝网络的准确知识 参与慢性心力衰竭发展的过程对 制定旨在抗击这一问题的创新治疗战略 衰弱综合症。

Congestive heart failure (CHE) is associated with impaired cardiocyte function. Alterations in the content and isoform distribution of contractile proteins and key proteins involved in calcium handling have been found in CHF. Decreased force development in CHF may result from altered calcium handling, reduced contractile protein function, or from a combination of these factors. The precise relationship between alterations in protein synthesis and impaired cardiocyte function in CHF, however, is still uncertain. The overall goal of the present research proposal is to determine the cellular mechanisms of reduced myocardial function in an experimental animal model of CHF. Our data indicates depressed function at end-stage CHF in both electrically stimulated and in skinned cardiac trabeculae an single skinned cardiocytes. Recent preliminary data, however, indicates that depressed twitch force of contraction precedes depressed myofilament function, suggesting that alterations in calcium handling early in the development of CHF induces depressed cardiac function, while changes in myofilament function are associated with the transition to overt heart failure. In this proposal, therefore, we will specifically test the hypotheses that 1) reduced myocardial force development during the development of CHF is caused by reduced intracellular calcium concentration during systole: Accurate and calibrated intracellular calcium will be measured directly in isolated cardiac trabeculae by fluorescence calcium probe under conditions of strict sarcomere length control using a recently developed technique; 2) The transition to decompensated end-stage CHF is caused by reduced maximum force development, calcium responsiveness, and ATP hydrolysis rate of the contractile apparatus: Force development, calcium responsiveness, and ATP hydrolysis rate will be measured in permeabilized trabeculae as function of free calcium. Laser diffraction techniques will be used to accurately measure and control sarcomere length such that accurate and unambiguous data are obtained. Throughout the development of CHF, calcium handling protein and myofilament protein levels as well as gene expression will be assessed by Western and Northern blot, respectively, to correlate with in-situ functional and hemodynamic data. It is expected that these experiments will provide new and unambiguous data. Accurate knowledge regarding the cellular processes that participate in the development of CHF is critical to the development of innovative treatment strategies aimed to combat this debilitating syndrome.