CONTROL OF CARDIAC GROWTH BY CARDIAC GLYCOSIDES

强心苷对心脏生长的控制

• 批准号: 6564886
• 负责人: Zijian Xie
• 金额: $ 32.14万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-01 至 2003-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6564886
• 关键词: actins; age difference; cardiac glycosides; cell growth regulation; developmental genetics; enzyme mechanism; genetic transcription; heart cell; hypertrophic myocardiopathy; laboratory rat; muscle cells; myocardium; ouabain; protein kinase; protooncogene; sodium potassium exchanging ATPase; tissue /cell culture; transcription factor

Cardiac glycosides, which improve the force of cardiac contraction, have been the most widely used drugs in the therapy of heart failure. Recently, we have found that interactions of cardiac glycoside (.e.g., ouabain) with sarcolemmal NaK-ATPase not only affect contractility, but also generate signals that are transduced to the nucleus, altering the expressions of growth-related genes, and causing myocyte hypertrophy. Because growth abnormalities of myocytes and other heart cells are involved in the development of heart failure, we now propose to extend our initial discoveries along the following lines: In studies of Specific Aim 1, cultured neonatal rat cardiac myocytes will be used to define ouabain- initiated transduction pathways that lead to the transcriptional regulations of two growth-related genes of these myocytes. The two model genes are c-fos and those of skeletal alpha-actin. The studies are designed to clarify the roles of Ca2+ and several protein kinases and transcription factors in these pathways, as suggested by our recent findings. Studies of Specific Aim 2 are designed to identify interactions (cross-talk) between the above ouabain-initiated pathways and the gene regulation pathways of several well-established hypertrophic stimuli; and to determine if such interactions lead to additive, synergistic, or antagonistic effects of ouabain and the other stimuli on myocyte growth. In specific Aim 3, we plan to begin the extension for our studies from cellular level to higher levels of complexity by comparing the growth- related effects of ouabain in neonatal myocytes with those in adult myocytes, and in isolated hearts obtained from normal rats and rats whose hearts are subjected to pressure or volume overload. In studies of Specific Aim 4, ouabain-induced effects on myocytes will be compared with those of low extracellular K+ and antisense-induced down-regulation of Nak-ATPase to determine if the mode of inhibition of NaK-ATPase affects the pathways of cardiac gene regulation. We expect that these basic studies, along with the ongoing studies of others on pathophysiological mechanisms of cardiac hypertrophy, will contribute to the understanding of the processes involved in transit from cardiac hypertrophy to heart failure.

强心甙具有增强心脏收缩力的作用 是治疗心力衰竭应用最广泛的药物。最近， 我们发现强心苷（例如哇巴因）与 肌膜 NaK-ATP 酶不仅影响收缩力，还产生 信号转导至细胞核，改变表达 生长相关基因，并导致心肌细胞肥大。因为成长 心肌细胞和其他心脏细胞的异常参与 心力衰竭的发展，我们现在建议延长我们的初步 发现如下：在具体目标 1 的研究中， 培养的新生大鼠心肌细胞将用于定义哇巴因- 启动转导途径，导致转录 这些肌细胞的两个生长相关基因的调节。两种型号 基因是c-fos 和骨骼α-肌动蛋白的基因。这些研究是 旨在阐明 Ca2+ 和几种蛋白激酶的作用， 正如我们最近的研究表明的，这些途径中的转录因子 发现。具体目标 2 的研究旨在识别相互作用 上述哇巴因引发的途径和基因之间的（串扰） 几种成熟的肥大刺激的调节途径；和 以确定这种相互作用是否会导致相加、协同或 哇巴因和其他刺激物对心肌细胞生长的拮抗作用。 在具体目标 3 中，我们计划从 通过比较生长-细胞水平到更高水平的复杂性 哇巴因对新生儿肌细胞与成人肌细胞的相关影响 心肌细胞，以及从正常大鼠和大鼠中获得的离体心脏 心脏承受压力或容量超负荷。在研究中 具体目标 4，哇巴因对心肌细胞的诱导作用将与 低细胞外 K+ 和反义诱导的下调 Nak-ATPase 以确定 NaK-ATPase 的抑制模式是否影响 心脏基因调控途径。我们期望这些基本的 研究以及其他人正在进行的病理生理学研究 心脏肥大的机制，将有助于理解 从心脏肥大到心脏的转变过程 失败。