MYOCARDIAL RELAXATION AND CA++ TRANSPORT IN HYPERTROPHY

心肌肥厚时的心肌舒张和 CA 转运

• 批准号: 2872927
• 负责人: PAUL C SIMPSON
• 金额: $ 21.82万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-02-01 至 2002-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2872927
• 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

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 拟议的研究是为了确定导致受损的机制 左心室肥厚 (LVH) 中的舒张和 Ca2+ 处理以及 开发有效的疗法来逆转这些异常。 申请人 解决三个主要问题。 首先，导致速度减慢的机制 松弛是 LVH 心功能障碍的一个重要因素，仍然存在 不确定。 游离胞质 [Ca2+] ([Ca2+]c) 下降速度减慢 据报道，这表明这可能是一个因素。 但资料很少 显示松弛与 [Ca2+]c 下降之间存在密切关系 将支持因果关系。 此外，[Ca2+]c并不直接表明 Ca2+ 激活收缩蛋白的程度。 第二， 尽管 SR Ca2+-ATPase 的活性和含量异常 与减缓 LVH 中的 [Ca2+]c 下降有关，[Ca2+]c 与 LVH 之间存在密切联系 下降，SR Ca2+-ATPase 尚未建立。 三、目前 现有治疗 LVH 心功能不全的疗法无效。 初步数据表明，甲状腺激素可逆转放松减慢和 即使在病理性 LVH 发生后开始治疗，[Ca2+]c 仍下降 尽管压力持续超载，但仍然成立。 为了解决这些 问题，将检验三个主要假设： 1. 心肌减慢 松弛主要是由 [Ca2+]c 下降速度减慢引起的。 2.[Ca2+]c下降减慢是由功能和/或水平异常引起的 SR Ca2+-ATP酶。 3. 甲状腺激素加速松弛和[Ca2+]c 病理性 LVH 下降。 等容心脏（大鼠）将用于 建立 [Ca2+]c（indo-1 荧光）与 LVH 舒张之间的联系 （压力过载）。 肌肉条将用于确定是否 Ca2+激活减慢是减缓Ca2+激活的基本机制 LVH 的放松。 SR Ca2+ 摄取和 SR Ca2+-ATPase 水平及其 调节蛋白，受磷蛋白，将使用肌细胞进行评估（Western 印迹）。