CARDIAC NA/CA EXCHANGER HYPERTROPHIC REGULATION

心肌细胞通过增强细胞对增加的血流动力学负荷作出反应 质量和特定基因表达的变化，导致收缩 功能障碍在早期压力超负荷心肌肥厚中， 收缩功能障碍可能主要是由于增加的微管 增加肌节运动的内部阻力的形成。在 晚期肥大和衰竭，收缩功能进一步受损 通过改变Ca 2+的稳态。我们确定 Na-Ca交换器信息的快速上调在 转录水平，在整个期间保持上调 肥大性生长并导致交换蛋白增加， 活动我们已经确定了所需的顺式元素， ncxl基因在心脏中的表达。重要的是，我们还 发现了一种新的元素，不仅是心脏所需的， 表达，但重要的是交换上调。我们到了 在一个很好的位置来检查介导的分子机制， 交换器表达对血流动力学负荷的响应。此外，我们还可以 使用转基因小鼠，直接解决是否向上的问题， 钠钙交换的调节是胚胎发育的重演的一部分。 表达是否由肥大触发或其上调是否是 由SR下降引起的Ca 2+稳态变化引发 Ca 2 +- ATPase表达和活性。最后，考虑到交换器是 Ca 2+外流的主要机制，令人惊讶的是， 已知交换器活性是如何调节的。我们已经发现 在成年心肌细胞中， 蛋白磷酸酶的抑制。初步数据显示， 交换剂的调节可以通过与 细胞骨架成分调节钙-钙的细胞因子有哪些 成人心肌细胞中的交换活性以及它们如何介导 正常和肥厚心脏中的交换活性？具体 该提案的目标是：1）表征顺式调节 2）识别和描述反作用因素 负责NXC 1的心脏特异性和负荷诱导的调节 基因，和3）开始表征的调控钠钙交换 心脏肥大的活动。这项工作提供了一个独特的机会 为了深入了解一个基因的转录调控， 产品是至关重要的钙稳态和了解如何交换 在正常和肥大的心脏中调节活动。

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.