MYOCARDIAL RELAXATION AND CA++ TRANSPORT IN HYPERTROPHY

心肌肥厚时的心肌舒张和 CA 转运

• 批准号: 6151319
• 负责人: PAUL C SIMPSON
• 金额: $ 22.48万
• 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/6151319
• 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）： 拟议的研究是确定导致受损的机制， 左心室肥厚（LVH）的舒张和Ca 2+处理， 开发有效的疗法来逆转这些异常。 申请人 解决了三个主要问题。 第一，导致减速的机制 舒张是LVH心功能障碍的重要因素， 不确定 细胞内游离[Ca 2 +]（[Ca 2 +]c）下降的减缓， 据报道，这可能是一个因素。 但几乎没有数据 显示放松与[Ca 2 +]c下降之间存在密切关系， 会支持因果关系 此外，[Ca 2 +]c并不直接表明 收缩蛋白被Ca 2+激活的程度。 第二、 尽管SR Ca ~（2+）-ATP酶的活性和含量异常， 与减缓LVH中[Ca 2 +]c下降有关，[Ca 2 +] c与LVH中[Ca 2 +]c SR Ca ~（2+）-ATP酶未建立。 第三，目前 LVH中心脏功能障碍的可用疗法是无效的。 初步数据表明，甲状腺激素逆转减缓了舒张， [Ca2+]c下降，即使治疗开始后，病理性LVH是 尽管持续的压力过载， 解决这些 问题，三个主要假设将被测试：1。 心肌减慢 松弛主要是由[Ca 2 +]c下降速率的减慢引起的。 2. [Ca 2 +]c下降的减缓是由功能和/或水平异常引起的 SR Ca ~（2+）-ATP酶的活性。 3. 甲状腺激素加速舒张和[Ca 2 +]c 病理性LVH下降。 等容心脏（大鼠）将用于 建立[Ca 2 +]c（indo-1荧光）与LVH松弛之间联系 （压力过载）。 肌肉条将用于确定是否 Ca 2+激活的减缓是减缓 LVH的松弛。 肌浆网Ca ~（2+）摄取和肌浆网Ca ~（2+）-ATP酶水平， 将使用肌细胞（Western blot）评估调节蛋白受磷蛋白（phospholamban 印迹）。