CARDIAC NA/CA EXCHANGER HYPERTROPHIC REGULATION

心脏 NA/CA 交换器肥厚调节

• 批准号: 6631280
• 负责人: Donald R. Menick
• 金额: $ 29万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6631280
• 关键词: calcium flux; calcium ion; calcium transporting ATPase; cardiac myocytes; cats; disease /disorder model; genetic regulation; genetic regulatory element; genetically modified animals; heart contraction; hemodynamics; hypertrophic myocardiopathy; laboratory mouse; laboratory rat; membrane transport proteins; microtubules; phosphatase inhibitor; phosphoprotein phosphatase; regulatory gene; sarcomeres; sodium ion; transcription factor

The cardiocyte responds to increased hemodynamic loading by augmented cell mass and by changes in specific gene expression that result in contractile dysfunction. In early pressure overload cardiac hypertrophy this contractile dysfunction may be primarily due to the increased microtubule formation that increases the internal resistance to sarcomere motion. In late hypertrophy and failure, contractile function is further compromised in the cardiomyocyte by changes in Ca2+ homeostasis. We determined that the rapid upregulation of Na-Ca exchanger message is regulated at the transcriptional level, remains up-regulated throughout the period of hypertrophic growth and results in increased exchanger protein and activity. We have identified the cis elements which are required for expression of the ncxl gene in the heart. Importantly, we have also discovered a novel element that is not only required for cardiac expression but is important for the exchanger up-regulation. Here we are in an excellent position to examine the molecular mechanisms which mediate exchanger expression in response to hemodynamic load. In addition, we can directly address, using transgenic mice, the question of whether up- regulation of the Na-Ca exchange is part of a recapitulation of embryonic expression triggered by hypertrophy or whether its up-regulation is triggered by changes in Ca2+ homeostasis brought about by the drop in SR Ca2+- ATPase expression and activity. Lastly, given that the exchanger is the predominant mechanism for Ca2+ efflux, it is surprising that so little is known about how the exchanger activity is regulated. We have discovered that exchanger activity is dramatically affected in adult cardiocytes by inhibition of protein phosphatases. Preliminary data indicate that this regulation of the exchanger may be mediated by interaction with cytoskeletal elements. What are the cellular factors that regulate Ca-Ca exchanger activity in the adult cardiocyte and how do they mediate exchanger activity in the normal and hypertrophic heart? The specific objectives of the proposal are: 1) characterize the cis-regulatory elements and 2) identify and characterize the trans-acting factors responsible for cardiac-specific and load-induced regulation of the nxc1 gene, and 3) begin to characterize the regulation of Na-Ca exchanger activity in cardiac hypertrophy. This work presents a unique opportunity to gain insight into the transcriptional regulation of a gene whose product is critical to calcium homeostasis and understand how exchanger activity is regulated in the normal and hypertrophied heart.

心肌细胞对增大的细胞所增加的血流动力学负荷作出反应 质量和导致收缩的特定基因表达的变化 功能障碍。在早期压力超负荷心肌肥厚 收缩功能障碍可能主要是由于微管的增加。 增加肌节运动的内部阻力的队形。在……里面 晚期肥大和衰竭，收缩功能进一步受损 通过改变心肌细胞内钙离子的动态平衡。我们决定 钠钙交换报文的快速上调在 转录水平，在整个时期保持上调。 肥大生长并导致交换器蛋白和 活动。我们已经确定了以下所需的配置文件元素 Ncx1基因在心脏中的表达。重要的是，我们还 发现了一种新元素，它不仅是心脏所必需的 表达，但对于交换器的上调很重要。我们到了 处于一个很好的位置来研究中介分子机制 血流动力学负荷时交换器的表达。此外，我们还可以 利用转基因小鼠，直接解决是否向上- 钠钙交换的调节是胚胎发育过程的一部分 肥大引发的表达或其上调是否 由肌浆网下降引起的钙稳态变化触发 Ca~(2+)-ATPase表达和活性。最后，假设交换器是 钙外流的主要机制，令人惊讶的是，如此之少 知道交易所的活动是如何被调节的。我们发现 这种交换器的活性在成人心肌细胞中受到显著影响 蛋白磷酸酶抑制。初步数据显示，这 对交换器的调节可以通过与 细胞骨架元素。调节钙-钙的细胞因子是什么 成人心肌细胞中的交换器活性及其调节机制 正常和肥厚心脏中的交换器活性？具体的 该提案的目标是：1)描述顺式监管的特征 要素和2)识别和表征反式作用因素 负责心脏特异性和负荷诱导的Nxc1调节 基因，以及3)开始表征钠钙交换的调节。 心肌肥厚的活动性。这项工作提供了一个独特的机会 为了深入了解其基因的转录调控 产品对钙稳态至关重要，并了解交换器是如何 活动在正常和肥厚的心脏中受到调节。