CONTROL OF CARDIAC GROWTH BY CARDIAC GLYCOSIDES

强心苷对心脏生长的控制

• 批准号: 6109831
• 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: 1999
• 资助国家: 美国
• 起止时间: 1999-03-01 至 2000-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6109831
• 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.

改善心脏收缩力的心糖苷类药物