CONTROL OF CARDIAC GROWTH BY CARDIAC GLYCOSIDES

强心苷对心脏生长的控制

• 批准号: 6302213
• 负责人: Zijian Xie
• 金额: $ 15.82万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-01 至 2001-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6302213
• 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.

强心苷，提高心脏收缩力， 是治疗心力衰竭最广泛使用的药物。最近， 我们已经发现强心苷的相互作用（例如，哇巴因）与 肌膜NaK-ATP酶不仅影响肌的收缩性， 信号被传递到细胞核，改变了 生长相关基因，并导致肌细胞肥大。因为增长 心肌细胞和其他心脏细胞的异常参与了 心力衰竭的发展，我们现在建议延长我们最初的 发现沿着以下路线：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， 启动的转导途径，导致转录 这些肌细胞的两个生长相关基因的调节。两个模型 基因是c-fos和骨骼α-肌动蛋白的基因。这些研究 旨在阐明Ca 2+和几种蛋白激酶的作用， 转录因子在这些途径中，正如我们最近的研究所表明的那样， 调查结果。具体目标2的研究旨在确定相互作用 （串扰）之间的上述哇巴因启动途径和基因 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导致加和、协同或 哇巴因和其他刺激物对肌细胞生长的拮抗作用。 在具体目标3中，我们计划开始从 细胞水平到更高水平的复杂性，通过比较增长- 哇巴因对新生大鼠心肌细胞和成人心肌细胞作用的相关性 心肌细胞，以及从正常大鼠和 心脏承受压力或容量超负荷。研究中 具体目标4，将哇巴因诱导的对肌细胞的作用与 低细胞外K+和反义诱导的下调 NaK-ATP酶，以确定NaK-ATP酶的抑制模式是否影响 心脏基因调控的途径我们希望这些基本的 研究，沿着其他人正在进行的病理生理学研究 心脏肥大的机制，将有助于了解 从心脏肥大到心脏的转变过程 失败