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MYOCARDIAL RELAXATION AND CA++ TRANSPORT IN HYPERTROPHY

心肌肥厚时的心肌舒张和 CA 转运

基本信息

批准号：
6351490
负责人：
PAUL C SIMPSON
金额：
$ 23.15万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-02-01 至 2004-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6351490
关键词：
calcium flux calcium transporting ATPase cardiac myocytes enzyme activity hormone regulation /control mechanism laboratory rat muscle relaxation myocardium phospholamban sarcoplasmic reticulum thyroid hormones tissue /cell culture ventricular hypertrophy

项目摘要

DESCRIPTION (adapted from the applicant's abstract): The overall goal of the proposed research is to determine the mechanisms that cause impaired relaxation and Ca2+ handling in left ventricular hypertrophy (LVH) and to develop effective therapies to reverse these abnormalities. The applicant addresses three major problems. First, the mechanisms that cause slowing of relaxation, an important element of cardiac dysfunction in LVH, remain uncertain. Slowing of the decline of free cytosolic [Ca2+] ([Ca2+]c) has been reported, suggesting this may be a factor. But there are little data showing a close relationship between relaxation and [Ca2+]c decline that would support causality. Furthermore, [Ca2+]c does not directly indicate the extent to which the contractile proteins are activated by Ca2+. Second, although abnormal activity and content of SR Ca2+-ATPase have been implicated in slowing [Ca2+]c decline in LVH, a close link between [Ca2+]c decline and SR Ca2+-ATPase has not been established. Third, currently available therapies for cardiac dysfunction in LVH are not effective. Preliminary data suggest that thyroid hormone reverses slowed relaxation and [Ca2+]c decline even though treatment was started after pathological LVH was established, and despite continued pressure-overload. To address these issues, three major hypothesis will be tested: 1. Slowing of myocardial relaxation is primarily caused by slowing of the rate of [Ca2+]c decline. 2. Slowing of [Ca2+]c decline is caused by abnormal function and/or levels of SR Ca2+-ATPase. 3. Thyroid hormone accelerates relaxation and [Ca2+]c decline in pathological LVH. Isovolumic hearts (rat) will be used to establish a link between [Ca2+]c (indo-1 fluorescence) and relaxation in LVH (pressure-overload). Muscle strips will be used to determine whether slowing of Ca2+-activation is the fundamental mechanism that slows relaxation in LVH. SR Ca2+ uptake and levels of SR Ca2+-ATPase, and its regulatory protein, phospholamban, will be assessed using myocytes (Western blots).

描述(改编自申请人的摘要)：总体目标这项拟议的研究是为了确定导致损伤的机制左心室肥厚和TO的松弛和钙处理开发有效的治疗方法来逆转这些异常。申请人解决了三个主要问题。首先，导致减速的机制心肌松弛是左心室肥厚患者心功能不全的一个重要因素不确定。延缓细胞内游离钙浓度([Ca~(2+)]_c)的下降已经有报道，这表明这可能是一个因素。但几乎没有数据表明松弛与[Ca~(2+)]c下降有密切关系会支持因果关系。此外，[Ca~(2+)]_c并不直接表明钙离子激活收缩蛋白的程度。第二, 尽管肌质网钙-三磷酸腺苷酶活性和含量出现异常与减缓左心室肥厚[Ca~(2+)]_c的下降有关，[Ca~(2+)]_c之间的密切联系下降和肌浆网钙-ATPase尚未建立。第三，目前现有的治疗左心室肥厚患者心功能不全的方法并不有效。初步数据表明，甲状腺激素的逆转减缓了放松和 [Ca~(2+)]c下降，即使在病理性左心室肥厚后开始治疗已经确立，尽管压力持续超载。要解决这些问题问题，将检验三个主要假设：1.心肌细胞减慢松弛主要是由于[Ca~(2+)]_c下降速度减慢所致。 2.[Ca~(2+)]_c下降缓慢是由于功能和/或水平异常所致肌浆网Ca~(2+)-ATPase。3.甲状腺激素促进松弛和[Ca2+]c 病理性左心室肥厚下降。等容心脏(大鼠)将用于 [Ca~(2+)]_c(Indo-1荧光)与左心室肥厚松弛之间的联系 (压力-过载)。肌肉条将被用来确定钙离子激活减慢是减慢的根本机制左心室肥厚的松弛。肌浆网钙摄取和肌浆网钙-三磷酸腺苷酶水平及其意义调节蛋白，磷蛋白，将使用心肌细胞(Western)进行评估斑点)。