CONTROL OF CARDIAC GROWTH BY CARDIAC GLYCOSIDES

能增强心脏收缩力量的强心苷类药物 是心力衰竭治疗中应用最广泛的药物。最近， 我们已经发现，强心苷(如哇巴因)与 肌膜NAK-ATPase不仅影响收缩能力，而且还能产生 被传递到细胞核的信号，改变了 生长相关基因，并引起心肌细胞肥大。因为增长 心肌细胞和其他心肌细胞的异常参与了 心力衰竭的发展，我们现在建议延长我们最初的 沿着以下路线的发现：在对特定目标的研究1中， 培养的新生大鼠心肌细胞将被用来定义哇巴因- 启动的转导通路导致转录 这些心肌细胞的两个生长相关基因的调控。这两种模式 C-fos基因和骨骼α-肌动蛋白基因。这些研究是 旨在阐明钙离子和几种蛋白激酶的作用以及 这些途径中的转录因子，正如我们最近提出的那样 调查结果。对特定目标2的研究旨在确定相互作用 (串扰)上述哇巴因启动的通路和基因之间 几种成熟的肥大刺激的调节途径；以及 确定这种相互作用是否会导致相加、协同或 哇巴因等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 通过比较细胞级别和更高级别的复杂性 哇巴因对新生儿和成人心肌细胞的相关作用 心肌细胞，取自正常大鼠和大鼠心脏。 心脏受到压力或容量超负荷的影响。在…的研究中 具体目标4，哇巴因对心肌细胞的诱导作用将与 低细胞外钾和反义诱导的细胞外K+的表达下调 NAK-ATPase确定NAK-ATPase的抑制方式是否影响 心脏基因调控的途径。我们预计这些基本的 研究，以及其他正在进行的关于病理生理学的研究 心肌肥厚的机制，将有助于理解 心肌肥厚向心脏转化过程的研究进展 失败了。

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.