TRANSMURAL REGULATION Na/K PUMP ACTIVITY IN HEART

跨壁调节 心脏中的 Na/K 泵活动

• 批准号: 7128820
• 负责人: Richard T Mathias
• 金额: $ 38.75万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-15 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7128820
• 关键词: action potentials; angiotensin II; biological signal transduction; calcium flux; dogs; endocardium; heart contraction; heart electrical activity; muscle proteins; pericardium; renin angiotensin system; sodium potassium exchanging ATPase; voltage /patch clamp; voltage gated channel

DESCRIPTION (provided by applicant): Gao et al. (2005) found the max turn over rate (Vmax) of the Na/K pumps is spatially regulated across the canine ventricular wall, with Vmax being largest in the epicardium (Epi), intermediate in the midmyocardium (Mid) and smallest in the endocardium (Endo). Moreover, this study reported the transmural gradient in Vmax creates a gradient in [Na+]j, which is highest in Endo, intermediate in mid and lowest in Epi. Our preliminary data suggest the gradient in [Na+]j alters Na/Ca exchange (NCX) to generate a transmural gradient in [Ca2+]( and contraction. Preliminary data also suggest this transmural gradient is generated through angiotensin II (A2), which appears to be regulated by mechanical feedback, possible by the titin kinase (TiK), which is a mechanical sensor. We have created a quantitative model relating Na/K pump current (IP), lNCx, [Ca2*]j and contraction. The model successfully predicts differences in contraction and Ca-transients recorded in myocytes from Endo and Epi. Based on these data, we hypothesize: 1) The purpose of the transmural gradient in Vmax is to generate maximum contractility and rate responsiveness in Endo, which contracts first and against the greatest pressure load during each action potential (AP). 2) This is a feedback control system in which the sensor is the TiK. Pressure dependent activation of TiK causes up regulation of an autocrine renin angiotensin system (RAS) that sets the gradient in max IP such that [Ca2+]j and hence contractility offsets transmural gradients in load. The aims of this proposal are to test these two hypotheses. We will use a combination of electrophysiological, Na- and Ca-imaging, contraction, and biochemical measurements to accomplish these aims.

描述（由申请人提供）：Gao 等人。 (2005) 发现 Na/K 泵的最大周转率 (Vmax) 在犬心室壁上受到空间调节，Vmax 在心外膜 (Epi) 中最大，在心肌中层 (Mid) 中居中，在心内膜中最小（远藤）。此外，这项研究报告称，Vmax 的透壁梯度产生了 [Na+]j 的梯度，Endo 最高，中部居中，Epi 最低。我们的初步数据表明 [Na+]j 中的梯度改变 Na/Ca 交换 (NCX)，从而产生 [Ca2+]( 和收缩中的透壁梯度。初步数据还表明，这种透壁梯度是通过血管紧张素 II (A2) 产生的，它出现通过机械反馈进行调节，可能通过肌动蛋白激酶 (TiK)（一种机械传感器）进行调节。我们创建了一个与 Na/K 泵电流 (IP)、lNCx、[Ca2*]j 相关的定量模型。该模型成功预测了 Endo 和 Epi 心肌细胞中记录的收缩和 Ca 瞬变的差异，基于这些数据，我们假设：1) Vmax 中的透壁梯度的目的是在 Endo 中产生最大的收缩性和速率反应性。 ，在每个动作电位 (AP) 期间，它首先收缩并抵抗最大的压力负载。 2）这是一个反馈控制系统，其中传感器是TiK。 TiK 的压力依赖性激活导致自分泌肾素血管紧张素系统 (RAS) 的上调，该系统设置最大 IP 的梯度，使得 [Ca2+]j 和收缩性抵消负载的跨壁梯度。该提案的目的是检验这两个假设。我们将结合电生理学、钠和钙成像、收缩和生化测量来实现这些目标。